Highly Compactable and Durable Direct Compression Excipients and Excipient Systems

ABSTRACT

The present invention relates to solid dispersions including, but not limited to, co-processed carbohydrates with different solubilities and concentrations, which have a microcrystalline plate structure. The solid dispersions, excipient systems and formulations of the present invention are highly compactable and durable and when compressed into solid dosage forms demonstrate uniform densification, low friability at low pressures, and and/or relatively constant low disintegration times at various hardnesses. The solid dosage forms of the present invention demonstrate superior organoleptics, disintegration, and/or robustness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/158,566 filed Mar. 9, 2009, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to a highly compactable and durable soliddispersion, and excipient system made therefrom, comprising co-processedcarbohydrates which have different solubilities and/or concentrations,and microcrystalline plate structure, and formulations producedtherefrom, which formulations are directly compressible into soliddosage forms. In some embodiments of the present invention the soliddosage forms demonstrate superior organoleptics, fast disintegration,and/or good robustness. In some embodiments the present invention alsoincludes, but is not limited to, the solid dosage forms produced bydirectly compressing the co-processed solid dispersion and/or excipientsystem.

In some embodiments, the present invention also relates to soliddispersions of co-processed carbohydrates that produce formulations thatare directly compressible into solid dosage forms, which soliddispersions have a microcrystalline plate structure.

BACKGROUND OF THE INVENTION

Existing excipients and excipient systems, such as commerciallyavailable directly compressible mannitol products require higherpressures to achieve a packagable tablet. As a result, there can be aloss in disintegration time caused by loss of porosity at similarhardness. Insoluble filler-binders, such as microcrystalline cellulose,can be used to make acceptable tablets at lower pressures but may leadto poor stability and/or dissolution and have poor mouth feel. Higherpressures may lead to the rupturing of many coated active pharmaceuticalingredients (APIs). High percentage sorbitol (>6%) products are moreacceptable from a pressure profile but may lead to poor stability andrequire higher levels of disintegrants to reach a less than 60 seconddisintegration time. The higher pressure needed for tablet durabilityrestricts the coating type, coating formulation and thickness of coatingthat can be used on the API in oral dispersible tablets. Thisrestriction requires excipients and coatings that survive better duringthe compaction process. Many sparingly soluble APIs are micronized. Itis important to maintain surface area for these APIs to obtain thedesired dissolution profile. Higher pressure can cause agglomeration ofmicronized APIs in the compression step and the merging of API particlesand loss of surface area. Some APIs such as aspirin are very soft anddeformable, and during compression pressure relocate these soft APIs tothe tablet surface especially in smaller sized tablets. It is importantto use low pressure excipients that are water soluble that can also flowreadily with the API with compression pressure in order to maintain thedisintegration and subsequent dissolution time of the tablet and preventtablet surfaces from becoming hydrophobic by the API movement.

BRIEF SUMMARY OF THE INVENTION

One embodiment of the present invention relates to a highly compactablesolid dispersion and excipient system including, but not limited to,co-processed carbohydrates which have different solubilities and whichform a layered microcrystalline plate structure, and formulationsproduced therefrom. In one embodiment, such formulations are directlycompressible into solid dosage forms, some of which demonstrate superiororganoleptics, disintegration, and/or robustness. In one embodiment, theinvention also includes, but is not limited to, solid dosage formsproduced by directly compressing the co-processed solid dispersionexcipient system. In one embodiment, the present invention also relatesto solid dispersions of co-processed carbohydrates that produceformulations that are directly compressible into solid dosage forms.

In one embodiment, the microcrystalline plate structure of the soliddispersion of the present invention allows for the production of soliddosage forms having uniform densification, low friability at lowpressures, and/or relatively constant low disintegration times atvarious hardnesses.

According to some embodiments of the invention, a solid dispersionincludes a mixture of at least two carbohydrates, wherein a firstcarbohydrate is present in an amount of about 70 wt % to about 99.5 wt %and a second carbohydrate is present in an amount of about 0.5 wt % toabout 30 wt %. In some embodiments, the first and/or secondcarbohydrates include polyols. In certain embodiments, the at least twocarbohydrates are co-spray dried. In some embodiments, a soliddispersion including a mixture of at least two carbohydrates is includedin a pharmaceutical formulation.

In some embodiments, the carbohydrates include mannitol, maltitol,isomalt and/or sorbitol. In some embodiments, the first carbohydrateincludes mannitol and the second carbohydrate includes maltitol. Incertain embodiments, mannitol and maltitol are present in a ratio ofabout 88:12 to about 99.5:0.5. In some embodiments, an excipient systemincludes a solid dispersion and a disintegrant, such as crospovidone.

According to some embodiments, a solid dispersion includes at leastthree carbohydrates, wherein a first carbohydrate is present in anamount of about 70 wt % to about 99.5 wt %, a second carbohydrate ispresent in an amount of about 0.5 wt % to about 30 wt %, and a thirdcarbohydrate is present an amount of about 0.5 wt % to about 30 wt %. Insome embodiments, the first, second, and/or third carbohydrates includepolyols. In some embodiments, the at least three carbohydrates areco-spray dried. In some embodiments the at least three carbohydrates arefluid bed granulated. In some embodiments, the at least threecarbohydrates are co-granulated. In some embodiments, the at least threecarbohydrates include mannitol, maltitol, lactitol, glucose, isomalt,and/or sorbitol. In certain embodiments, the first carbohydrate includesmannitol, the second carbohydrate includes maltitol, and the thirdcarbohydrate includes sorbitol. In some embodiments, a pharmaceuticalformulation includes a solid dispersion with a mixture of at least threecarbohydrates. In certain embodiments, an excipient system includes asolid dispersion and a disintegrant, such as crospovidone.

According to some embodiments, a solid dispersion includes a coatedcarbohydrate or carbohydrate mixture. In some embodiments, a coatedcarbohydrate includes a coated polyol and/or a coated sugar. In someembodiments, a coated carbohydrate mixture includes a coated polyolmixture and/or a coated sugar mixture. In some embodiments, an excipientsystem includes a coated polyol mixture. In certain embodiments, acoated polyol includes mannitol, such as spray dried mannitol. In someembodiments, a coated carbohydrate or coated carbohydrate mixture has acoating including, but not limited to a 60:40 copolymer ofvinylpyrrolidone and vinyl acetate. In some embodiments, an excipientsystem includes a solid dispersion and a disintegrant, such ascrospovidone. In some embodiments, a pharmaceutical formulation includesan excipient system with a coated carbohydrate or carbohydrate mixture.

According to some embodiments, a solid dispersion includes a mixture ofat least two carbohydrates, and a coated carbohydrate or carbohydratemixture. In some embodiments, the carbohydrates include polyols. In someembodiments, the at least two carbohydrates are co-spray dried. Incertain embodiments, the at least two carbohydrates are fluid bedgranulated. In certain embodiments, the at least two carbohydrates areco-granulated. In some embodiments, the at least two carbohydratesinclude mannitol, isomalt, maltitol, lactitol and/or sorbitol. In someembodiments, the at least two carbohydrates include about 70 wt % toabout 99.5 wt % mannitol and about 0.5 wt % to about 30 wt % maltitol.In some embodiments, the coated carbohydrate includes a coated polyoland/or a coated sugar. In some embodiments, the coated carbohydratemixture includes a coated sugar mixture and/or a coated polyol mixture.In certain embodiments, the coated carbohydrate has a coating including,but not limited to a 60:40 copolymer of vinylpyrrolidone and vinylacetate. In some embodiments, an excipient system including a mixture ofat least two carbohydrates, and a coated carbohydrate or carbohydratemixture further includes an active, a polyol, such as spray driedmannitol, and/or a disintegrant such as crospovidone. In someembodiments, a pharmaceutical formulation includes an excipient systemincluding a mixture of at least two carbohydrates, and coatedcarbohydrate or carbohydrate mixture. In some embodiments, apharmaceutical formulation includes about 25 wt % to about 99 wt % of anexcipient system.

According to some embodiments, an excipient system includes, but is notlimited to a mixture of at least three carbohydrates and a coated polyolor coated polyol mixture. In some embodiments, the at least threecarbohydrates include polyols. In some embodiments, the mixture of atleast three carbohydrates is co-spray dried or co-granulated. In certainembodiments, the mixture of at least three carbohydrates includesmannitol, maltitol, isomalt, and/or sorbitol. In certain embodiments,the at least three carbohydrates include about 70 wt % to about 99.5 wt% mannitol about 0.5 wt % to about 30 wt % maltitol, and about 0.5 wt %to about 30 wt % sorbitol. In some embodiments, the coated polyol has acoating including, but not limited to a 60:40 copolymer ofvinylpyrrolidone and vinyl acetate. In some embodiments, an excipientsystem including a solid dispersion of at least three carbohydrates anda coated polyol or coated polyol mixture, further includes an active, apolyol such as spray dried mannitol and/or a disintegrant such ascrospovidone.

In some embodiments, a pharmaceutical formulation includes an excipientsystem including a solid dispersion of at least three carbohydrates, anda coated carbohydrate or carbohydrate mixture. In some embodiments, apharmaceutical formulation further includes an active and/or adisintegrant such as crospovidone. In some embodiments, a pharmaceuticalformulation further includes about 25 wt % to about 99 wt % of anexcipient system.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the invention,there are shown in the drawings preferred embodiment(s). It should beunderstood, however, that the invention is not limited to the precisearrangements and instrumentalities shown. In the drawings:

FIG. 1 is a flow diagram depicting a process for co-sprayed fluid-bedspray drying.

FIG. 2 is a SEM (magnification 2000×) of Solid Dispersion A afterco-spray drying.

FIG. 3 is a scanning electron micrograph (SEM) (magnification 2000×) ofa broken cross section of Solid Dispersion A after compression intotablet.

FIG. 4 is a graph depicting hardness as a function of compression forcefor tableted Solid Dispersion A.

FIG. 5 is a graph depicting friability as a function of hardness fortableted Solid Dispersion A.

FIG. 6 , comprising FIGS. 6A-6K, is a set of SEMs of different mannitolcompositions after they are dried in spray dryer.

FIG. 6A is a SEM (magnification 100×) of spray dried mannitol Mannogem®EZ EP grade produced by SPI Pharma, Inc.

FIG. 6B represents FIG. 6A at 1000× magnification.

FIG. 6C represents FIG. 6A at 2000× magnification.

FIG. 6D is a SEM (magnification 100×) of spray dried mannitolMannogem®-EZ USP grade produced by SPI Pharma, Inc.

FIG. 6E represents FIG. 6D at 1000× magnification.

FIG. 6F represents FIG. 6D at 2000× magnification.

FIG. 6G is a SEM (magnification 100×) of spray dried mannitol HSproduced by SPI Pharma, Inc.

FIG. 6H represents FIG. 6G at 1000× magnification.

FIG. 6I represents FIG. 6G at 2000× magnification.

FIG. 6J is a SEM (magnification 1000×) of spray dried mannitol Parteck®M 200 EP grade produced by Merck KGaA.

FIG. 6K represents FIG. 6J at 2000× magnification.

FIG. 7 , comprising FIGS. 7A-7C, is a set of SEMs of Solid Dispersion Aafter co-spray drying.

FIG. 7A is a SEM (magnification 100×) of Solid Dispersion A.

FIG. 7B represents FIG. 7A at 1000× magnification.

FIG. 7C represents FIG. 7A at 2000× magnification.

FIG. 8 is a graph depicting hardness as a function of compression forcefor comparison of tableted Solid Dispersion A to other excipients.

FIG. 9 is a graph depicting disintegration as a function of compressionforce for comparison of tableted Solid Dispersion A to other excipients.

FIG. 10 is a drawing of an embodiment of the microcrystalline platestructure of the solid dispersion.

FIG. 11 is a graph depicting radial tensile strength as a function of %porosity for tableted Solid Dispersion A.

FIG. 12 is a graph depicting hardness as a function of % porosity fortableted Solid Dispersion A.

FIG. 13 is a graph depicting % friability as a function of % porosityfor tableted Solid Dispersion A.

FIG. 14 is a graph depicting hardness as a function of compression forcefor comparison of tableted Solid Dispersion A and Fast Flo® lactose(Wisconsin Dairies) formulations.

FIG. 15 is a graph depicting friability as a function of compressionforce for comparison of tableted Solid Dispersion A and Fast Flo®lactose (Wisconsin Dairies) formulations.

FIG. 16 is a graph depicting disintegration and friability as a functionof hardness for tabletted Excipient System A.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is exemplary and explanatory and isintended to provide further explanation of the invention describedherein. Other advantages, and novel features will be readily apparent tothose skilled in the art from the following detailed description of theinvention.

In one embodiment, the aim of the present invention was to overcome thedrawbacks of existing excipients and excipient systems and provideexcipient systems that increase compactability and tablet durability atlower compression forces, improve tablet hardness, stability, decreasedisintegration time and/or improve organoleptics. The benefit of havingdisintegration time become independent of compression force in theexcipient system allows for a greater robustness in the process formaking a tablet.

In one embodiment, it was surprisingly found that the co-processed soliddispersions, excipient systems and formulations of the present inventionare highly compactable and when compressed into solid dosage formsdemonstrate uniform densification, low friability at low pressures,and/or relatively constant low disintegration times at varioushardnesses. In one embodiment, the solid dosage forms of the presentinvention demonstrate superior organoleptics, fast disintegration,and/or good tablet robustness in chewable and oral dispersible tabletapplications.

In one embodiment, the present invention relates to highly compactableand durable direct compression solid dispersions and excipient systemscomprising co-processed carbohydrates, some of which have differentsolubilities, and form a microcrystalline plate structure, andformulations produced therefrom, which formulations are directlycompressible into solid dosage forms, some of which demonstrate superiororganoleptics, fast disintegration, and/or good robustness. In oneembodiment, the present invention relates to highly compactable anddurable direct compression solid dispersions and excipient systemscomprising co-processed carbohydrates, some of which have differentcarbohydrate concentrations, and form a microcrystalline platestructure. In one embodiment, the present invention also includes, butis not limited to, the solid dosage forms produced by directlycompressing the co-processed solid dispersion and/or excipient system.

In one embodiment, the present invention also relates to soliddispersions of co-processed carbohydrates that form particles having amicrocrystalline plate structure, and that produce formulations that aredirectly compressible into solid dosage forms.

In one embodiment, the microcrystalline plate structure of theco-processed carbohydrates of the solid dispersions of the presentinvention allow for the production of solid dosage forms having uniformdensification, low friability at low pressures, and/or relativelyconstant low disintegration times at various hardnesses.

In some embodiments, solid dosage forms of the present invention exhibitone or more of superior functionality such as tabletability,organoleptic characteristics, disintegration time, and a decreasedsensitivity to compaction pressures; an increase in compaction pressuremay result in a favorable decrease in friability and a surprisingly lowincrease in disintegration time. In some embodiments, an excipientsystem of the present invention is pH-independent. In some embodiments,an excipient system of the present invention is water dispersible.

Disintegration times related to excipient systems, pharmaceuticalformulations and solid dosage forms of the present invention may bemeasured according to USP 32, Chapter 701. Friability related toexcipient systems, pharmaceutical formulations and solid dosage forms ofthe present invention may be measured according to USP 32, Chapter 1216.Tablet breaking force related to excipient systems, pharmaceuticalformulations and solid dosage forms of the present invention may bemeasured according to USP 32, Chapter 1217. Oral disintegration time maybe measured as is considered the time taken for 1 orally-disintegratingtablet to disintegrate in the oral cavity of a panelist, as measuredfrom the time of placement of the tablet until the time of perception ofcomplete disintegration has occurred, as determined by the panelist. Aset of 10 panelist's (n=10) observations will be used to calculate amean and standard deviation of the oral disintegration time.

The present invention is described herein using several definitions, asset forth below and throughout the application.

DEFINITIONS

The term “about” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which it is used. Ifthere are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” shallmean up to plus or minus 10% of the particular value.

The phrase “completely dissolve or disintegrate” used in the context ofthe present invention, means that the solid dosage form dissolves ordisintegrates to an extent that the patient believes the solid dosageform to be completely dissolved or disintegrated. That is, the patientcan no longer detect any significant lumps or large particles of theoriginal solid dosage form. Instead, at the point in time when the soliddosage from has completely dissolved or disintegrated in the oral cavityof the patient, the solid dosage form preferably has a creamy andpleasant mouthfeel that is conducive to swallowing.

The terms “solid dosage form,” “tablet,” and “solid preparation” areused synonymously within the context of the present invention. Theseterms should be construed to include a compacted or compressed powdercomposition obtained by compressing or otherwise forming the compositionto form a solid having a defined shape.

The term “directly compressible” means that the composition can becompressed into tablet form on standard tabletting machines (including,but non limited to high speed tabletting machines) using standard (i.e.,without any specially machined, shaped or coated surfaces) punches anddies, without any significant amount of the composition adhering to thepunches and dies.

The term “oral cavity” should be construed to include, but should not belimited to the buccal cavity.

The term “co-processed carbohydrate” means the processing of at leasttwo carbohydrates together to make a single product. For example,mannitol and sorbitol may be co-spray dried by first preparing a singlesolution of mannitol and sorbitol. Another example includes theco-granulation of mannitol and sorbitol.

The term “microcrystalline plate structure” means layers of crystallineand/or eutectic amorphous deposits, preferably planar plates and mostpreferably laminar planar plates. Microplate layers have a thickness ofless than 5 microns, preferably less than 3 microns and most preferablyless than 1 micron. Microcrystalline plates are mainly made up of 0% ofa crystalline core, preferably 10% of a crystalline core, and mostpreferably 99.5% of a crystalline core and 100% of a eutectic mixturepreferably greater than 90% of a eutectic mixture and most preferablygreater than 0.5% of a eutectic mixture.

The term “solid dispersion” means a solid product consisting of acontinuous phase (the dispersant), and a dispersed phase, in which thesolid dispersion includes miscible components of different solubilitiesand/or concentrations. The dispersed phase can be also a continuousphase if the dispersant is a fully molecularly miscible eutectic withthe dispersant, a discontinuous partially miscible eutectic, or amixture of structured crystalline, or amorphous components incorporatedinto a fused structure in which the melting point of the soliddispersion is not lowered more than 5° C. from the melting point of thedispersant and the solid dispersion's heat of fusion is not reduced bymore than 40 J/gm from the heat of fusion of the dispersant.

The term “solid layered dispersion” means a solid dispersion structuredin layers. The primary and most significant layer is a crystalline orfirm first layer or core. This layer develops first based on saturationconditions or is added as a suspended particle, followed by acrystallization or co-crystallization of the dispersant with the nextmost insoluble dispersed phase. This can be followed by a third orfourth layer or more dispersed components co-crystallizing, thuscontaining the core material and previous dispersed component(s).

The term “formulation” shall be construed to include a solid dispersionand/or excipient system plus an active ingredient, lubricant, optionallya disintegrant, optionally a glidant, optionally a sweetner, optionallya flavor, optionally a color, and optionally other excipients.

It has been discovered that the existing processes, products, or systemsdirected towards rapid disintegration or dissolution in the mouth havelimitations in certain aspects. Specifically, until now it has beendifficult to produce a tablet at low compression forces that is robust(e.g., low friability, low ejection forces, sufficient hardness) enoughto be processed in high speed tabletting machines, especially at lowcompression pressures, and shipped in low cost packages, and at the sametime retain rapid disintegration or dissolution properties. This isespecially obvious when producing a tablet having high doses of activepharmaceutical ingredients (APIs) or when producing a tablet having APIscoated with different polymers, waxes, and the like for taste-masking,API protection, sustained release, and/or controlled release purposes.

In one embodiment, an advantage of the solid dispersions, excipientsystems and formulations of the present invention is that they can beformed into high quality tablets on standard tabletting machines(including high speed tableting machines such as those made by Killianor Korsh, capable of producing at least 75,000 tablets per hour) usingstandard punches and dies. The “standard” punches and dies referred toabove are far less expensive to produce and maintain than the coated(e.g., teflon-coated) punches and dies used to produce tablets fromformulations that are sticky or difficult to compress.

In one embodiment, the present invention overcomes these limitations byproducing solid dispersions of co-processed carbohydrates with differentsolubilities. In one embodiment, the present invention overcomes theselimitations by producing solid dispersions of co-processed carbohydrateswith different concentrations. In one embodiment, the present inventionovercomes these limitations by producing solid dispersions ofco-processed carbohydrates with a microcrystalline plate structure. Inone embodiment, the present invention overcomes these limitations byproducing solid dispersions of co-processed carbohydrates with differentsolubilities, and with a microcrystalline plate structure. In oneembodiment, the present invention overcomes these limitations byproducing solid dispersions of co-processed carbohydrates with differentconcentrations, and with a microcrystalline plate structure. In oneembodiment, the solid dispersion of the present invention formed fromthe co-processing of two or more carbohydrates is characterized by asingle peak of a DSC (Differential Scanning Calorimeter) measurement.

In one embodiment, the microcrystalline plate structure of the soliddispersion allows for the production of solid dosage forms havinguniform densification, low friability at low compression pressures,and/or relatively constant low disintegration times at varioushardnesses. In one embodiment, the solid dispersion of the presentinvention ultimately produces a formulation that is compressible into atablet. This tablet is robust enough to withstand stress of handlingduring production, packaging and transportation, without specialprocessing or handling, while retaining rapid disintegration ordissolution properties and/or superior organoleptic properties likecreamy smooth mouthfeel without any grittiness in the oral cavity.Further, in one embodiment, the present invention allows robust tabletsto be made without cracking the coating of API's, where the integrity ofthe coating is critical for taste and/or controlled release or entericfunctionality.

Carbohydrate Mixture

Carbohydrates useful in the present invention include, but are notlimited to polyols and sugars. Suitable polyols may include but are notlimited to sugar alcohols of the general formula CH₂OH—(CHOH)_(n)—CH₂OH,where n is 2 to 6, and preferably 3 to 6, and their dimeric anhydrides.In some embodiments, the polyols include, but are not limited tosorbitol, mannitol, xylitol, erythritol, maltitol, lactitol, isomalt,and mixtures thereof. In some embodiments, sugars include but are notlimited to lactose, fructose, dextrose, sucrose, maltose, and mixturesthereof. In some embodiments, suitable sugars include but are notlimited to xylose, melted over maltose and xylose melted over sucrose.In some embodiments, the solid dispersion does not include xylitol.

Components

The mannitol portion of the solid dispersion or excipient system can befrom any source, such as MANNOGEM™ powder (SPI Pharma, Inc., Wilmington,Del.). Other sources of mannitol powder include GETEC Mannitol powder(BRAZIL), and PEARLITOL™ (Roquette, FRANCE).

The maltitol portion of an excipient system can be from any source, suchas MR20 Amalty (Towa Chemical Industry Co., Ltd., Tokyo, JAPAN),Matlisorb® (Roquette, France) or Maltidex™ (Cargill, Inc.)

The sorbitol portion of the solid dispersion or excipient system can befrom any source, such as Neosorb® (Roquette, FRANCE) or Sorbidex™(Cargill, Inc.).

In some embodiments, a solid dispersion includes a first carbohydrateand a second carbohydrate. In some embodiments, the first carbohydrateincludes a polyol. In some embodiments, the second carbohydrate includesa polyol. In some embodiments, the first carbohydrate includes a sugar.In some embodiments, the second carbohydrate includes a sugar. In someembodiments, a solid dispersion of the present invention includes about80 wt % to about 99.5 wt % first carbohydrate and about 0.5 wt % toabout 20 wt % second carbohydrate. In some embodiments, a soliddispersion includes about 80 wt % first carbohydrate; about 80.5 wt %first carbohydrate; about 81 wt % first carbohydrate; about 81.5 wt %first carbohydrate; about 82 wt % first carbohydrate; about 82.5 wt %first carbohydrate; about 83 wt % first carbohydrate; about 83.5 wt %first carbohydrate; about 84 wt % first carbohydrate; about 84.5 wt %first carbohydrate; about 85 wt % first carbohydrate; about 85.5 wt %first carbohydrate; about 86 wt % first carbohydrate; about 86.5 wt %first carbohydrate; about 87 wt % first carbohydrate; about 87.5 wt %first carbohydrate; about 88 wt % first carbohydrate; about 88.5 wt %first carbohydrate; about 89 wt % first carbohydrate; about 89.5 wt %first carbohydrate; about 90 wt % first carbohydrate; about 90.5 wt %first carbohydrate; about 91 wt % first carbohydrate; about 91.5 wt %first carbohydrate; about 92 wt % first carbohydrate; about 92.5 wt %first carbohydrate; about 93 wt % first carbohydrate; about 93.5 wt %first carbohydrate; about 94 wt % first carbohydrate; about 94.5 wt %first carbohydrate; about 95 wt % first carbohydrate; about 95.5 wt %first carbohydrate; about 96 wt % first carbohydrate; about 96.5 wt %first carbohydrate; about 97 wt % first carbohydrate; about 97.5 wt %first carbohydrate; about 98.5 wt % first carbohydrate; about 99 wt %first carbohydrate; or about 99.5 wt % first carbohydrate. In someembodiments, a solid dispersion includes about 0.5 wt % secondcarbohydrate; about 1 wt % second carbohydrate; about 1.5 wt % secondcarbohydrate; about 2 wt % second carbohydrate; about 2.5 wt % secondcarbohydrate; about 3 wt % second carbohydrate; about 3.5 wt % secondcarbohydrate; about 4 wt % second carbohydrate; about 4.5 wt % secondcarbohydrate; about 5 wt % second carbohydrate; about 5.5 wt % secondcarbohydrate; about 6 wt % second carbohydrate; about 6.5 wt % secondcarbohydrate; about 7 wt % second carbohydrate; about 7.5 wt % secondcarbohydrate; about 8 wt % second carbohydrate; about 8.5 wt % secondcarbohydrate; about 9 wt % second carbohydrate; about 9.5 wt % secondcarbohydrate; about 10 wt % second carbohydrate; about 10.5 wt % secondcarbohydrate; about 11 wt % second carbohydrate; about 11.5 wt % secondcarbohydrate; about 12 wt % second carbohydrate; about 12.5 wt % secondcarbohydrate; about 13 wt % second carbohydrate; about 13.5 wt % secondcarbohydrate; about 14 wt % second carbohydrate; about 14.5 wt % secondcarbohydrate; about 15 wt % second carbohydrate; about 15.5 wt % secondcarbohydrate; about 16 wt % second carbohydrate; about 16.5 wt % secondcarbohydrate; about 17 wt % second carbohydrate; about 17.5 wt % secondcarbohydrate; about 18.5 wt % second carbohydrate; about 19 wt % secondcarbohydrate; about 19.5 wt % second carbohydrate; or about 20 wt %second carbohydrate.

In some embodiments, the ratio of first carbohydrate:second carbohydratecan range from about 99:1 to about 70:30. In some embodiments, the ratioof first carbohydrate:second carbohydrate can range from about 99:1 toabout 80:20; about 99:1 to about 85:15; about 99:1 to about 86:14; about99:1 to about 87:13; about 99:1 to about 88:12; about 99:1 to about89:11; about 99:1 to about 90:10; about 99:1 to about 91:9. In someembodiments, the first carbohydrate to second carbohydrate ratio isabout 80:20; about 85:15; about 87:13; about 88:12; about 89:11; about90:10, about 91:9; about 92:8; about 93:7; about 96:4; about 97:3; about98:2; or about 99:1.

In some embodiments, a solid dispersion of the present inventionincludes about 70 wt % to about 99.5 wt % mannitol and about 0.5 wt % toabout 30 wt % maltitol. In some embodiments, an excipient systemincludes about 70 wt % mannitol; about 70.5 wt %; about 71 wt %; about71.5 wt %; about 72 wt %; about 72.5 wt %; about 73 wt %; about 73.5 wt%; about 74 wt %; about 74.5 wt %; about 75 wt %; about 75.5 wt %; about76 wt %; about 76.5 wt %; about 77 wt %; about 77.5 wt %; about 78 wt %;about 78.5 wt %; about 79 wt %; about 79.5 wt %; about 80 wt % mannitol;about 80.5 wt % mannitol; about 81 wt % mannitol; about 81.5 wt %mannitol; about 82 wt % mannitol; about 82.5 wt % mannitol; about 83 wt% mannitol; about 83.5 wt % mannitol; about 84 wt % mannitol; about 84.5wt % mannitol; about 85 wt % mannitol; about 85.5 wt % mannitol; about86 wt % mannitol; about 86.5 wt % mannitol; about 87 wt % mannitol;about 87.5 wt % mannitol; about 88 wt % mannitol; about 88.5 wt %mannitol; about 89 wt % mannitol; about 89.5 wt % mannitol; about 90 wt% mannitol; about 90.5 wt % mannitol; about 91 wt % mannitol; about 91.5wt % mannitol; about 92 wt % mannitol; about 92.5 wt % mannitol; about93 wt % mannitol; about 93.5 wt % mannitol; about 94 wt % mannitol;about 94.5 wt % mannitol; about 95 wt % mannitol; about 95.5 wt %mannitol; about 96 wt % mannitol; about 96.5 wt % mannitol; about 97 wt% mannitol; about 97.5 wt % mannitol; about 98.5 wt % mannitol; about 99wt % mannitol; or about 99.5 wt % mannitol. In some embodiments, a soliddispersion includes about 0.5 wt % maltitol; about 1 wt % maltitol;about 1.5 wt % maltitol; about 2 wt % maltitol; about 2.5 wt % maltitol;about 3 wt % maltitol; about 3.5 wt % maltitol; about 4 wt % maltitol;about 4.5 wt % maltitol; about 5 wt % maltitol; about 5.5 wt % maltitol;about 6 wt % maltitol; about 6.5 wt % maltitol; about 7 wt % maltitol;about 7.5 wt % maltitol; about 8 wt % maltitol; about 8.5 wt % maltitol;about 9 wt % maltitol; about 9.5 wt % maltitol; about 10 wt % maltitol;about 10.5 wt % maltitol; about 11 wt % maltitol; about 11.5 wt %maltitol; about 12 wt % maltitol; about 12.5 wt % maltitol; about 13 wt% maltitol; about 13.5 wt % maltitol; about 14 wt % maltitol; about 14.5wt % maltitol; about 15 wt % maltitol; about 15.5 wt % maltitol; about16 wt % maltitol; about 16.5 wt % maltitol; about 17 wt % maltitol;about 17.5 wt % maltitol; about 18.5 wt % maltitol; about 19 wt %maltitol; about 19.5 wt % maltitol; about 20 wt % maltitol; about 20.5wt %; about 21 wt %; about 21.5 wt %; about 22 wt %; about 22.5 wt %;about 23 wt %; about 23.5 wt %; about 24 wt %; about 24.5 wt %; about 25wt %; about 25.5 wt %, about 26 wt %; about 26 wt %; about 26.5 wt %;about 27 wt %; about 27.5 wt %; about 28 wt %; about 28.5 wt %; about 29wt %; about 29.5 wt %; or about 30 wt %.

In some embodiments, the ratio of mannitol:maltitol can range from about99:1 to about 70:30. In some embodiments, the ratio of mannitol:maltitolcan range from about 99:1 to about 80:20; about 99:1 to about 85:15;about 99:1 to about 86:14; about 99:1 to about 87:13; about 99:1 toabout 88:12; about 99:1 to about 89:11; about 99:1 to about 90:10; about99:1 to about 91:9. In some embodiments, the mannitol to maltitol ratiois about 80:20; about 85:15; about 87:13; about 88:12; about 89:11;about 90:10, about 91:9; about 92:8; about 93:7; about 96:4; about 97:3;about 98:2; or about 99:1.

In some embodiments, a solid dispersion of the present inventionincludes about 80 wt % to about 99.5 wt % mannitol and about 0.5 wt % toabout 20 wt % isomalt. In some embodiments, an excipient system includesabout 80 wt % mannitol; about 80.5 wt % mannitol; about 81 wt %mannitol; about 81.5 wt % mannitol; about 82 wt % mannitol; about 82.5wt % mannitol; about 83 wt % mannitol; about 83.5 wt % mannitol; about84 wt % mannitol; about 84.5 wt % mannitol; about 85 wt % mannitol;about 85.5 wt % mannitol; about 86 wt % mannitol; about 86.5 wt %mannitol; about 87 wt % mannitol; about 87.5 wt % mannitol; about 88 wt% mannitol; about 88.5 wt % mannitol; about 89 wt % mannitol; about 89.5wt % mannitol; about 90 wt % mannitol; about 90.5 wt % mannitol; about91 wt % mannitol; about 91.5 wt % mannitol; about 92 wt % mannitol;about 92.5 wt % mannitol; about 93 wt % mannitol; about 93.5 wt %mannitol; about 94 wt % mannitol; about 94.5 wt % mannitol; about 95 wt% mannitol; about 95.5 wt % mannitol; about 96 wt % mannitol; about 96.5wt % mannitol; about 97 wt % mannitol; about 97.5 wt % mannitol; about98.5 wt % mannitol; about 99 wt % mannitol; or about 99.5 wt % mannitol.In some embodiments, an excipient system includes about 0.5 wt %isomalt; about 1 wt % isomalt; about 1.5 wt % isomalt; about 2 wt %isomalt; about 2.5 wt % isomalt; about 3 wt % isomalt; about 3.5 wt %isomalt; about 4 wt % isomalt; about 4.5 wt % isomalt; about 5 wt %isomalt; about 5.5 wt % isomalt; about 6 wt % isomalt; about 6.5 wt %isomalt; about 7 wt % isomalt; about 7.5 wt % isomalt; about 8 wt %isomalt; about 8.5 wt % isomalt; about 9 wt % isomalt; about 9.5 wt %isomalt; about 10 wt % isomalt; about 10.5 wt % isomalt; about 11 wt %isomalt; about 11.5 wt % isomalt; about 12 wt % isomalt; about 12.5 wt %isomalt; about 13 wt % isomalt; about 13.5 wt % isomalt; about 14 wt %isomalt; about 14.5 wt % isomalt; about 15 wt % isomalt; about 15.5 wt %isomalt; about 16 wt % isomalt; about 16.5 wt % isomalt; about 17 wt %isomalt; about 17.5 wt % isomalt; about 18.5 wt % isomalt; about 19 wt %isomalt; about 19.5 wt % isomalt; or about 20 wt % isomalt.

In some embodiments, the ratio of mannitol:isomalt can range from about99:1 to about 70:30. In some embodiments, the ratio of mannitol:isomaltcan range from about 99:1 to about 80:20; about 99:1 to about 85:15;about 99:1 to about 86:14; about 99:1 to about 87:13; about 99:1 toabout 88:12; about 99:1 to about 89:11; about 99:1 to about 90:10; about99:1 to about 91:9. In some embodiments, the mannitol to isomalt ratiois about 80:20; about 85:15; about 87:13; about 88:12; about 89:11;about 90:10, about 91:9; about 92:8; about 93:7; about 96:4; about 97:3;about 98:2; or about 99:1.

In some embodiments, a solid dispersion includes a first carbohydrate, asecond carbohydrate, and a third carbohydrate. In some embodiments, thefirst carbohydrate includes a polyol. In some embodiments, the secondcarbohydrate includes a polyol. In some embodiments, the thirdcarbohydrate includes a polyol. In some embodiments, the firstcarbohydrate includes a sugar. In some embodiments, the secondcarbohydrate includes a sugar. In some embodiments, the thirdcarbohydrate includes a sugar. In some embodiments, a solid dispersionincludes about 80 wt % to about 99.5 wt % first carbohydrate, about 0.5wt % to about 20 wt % second carbohydrate, and about 0.5 wt % to about20 wt % third carbohydrate. In some embodiments, a solid dispersionincludes about 80 wt % first carbohydrate; about 80.5 wt % firstcarbohydrate; about 81 wt % first carbohydrate; about 81.5 wt % firstcarbohydrate; about 82 wt % first carbohydrate; about 82.5 wt % firstcarbohydrate; about 83 wt % first carbohydrate; about 83.5 wt % firstcarbohydrate; about 84 wt % first carbohydrate; about 84.5 wt % firstcarbohydrate; about 85 wt % first carbohydrate; about 85.5 wt % firstcarbohydrate; about 86 wt % first carbohydrate; about 86.5 wt % firstcarbohydrate; about 87 wt % first carbohydrate; about 87.5 wt % firstcarbohydrate; about 88 wt % first carbohydrate; about 88.5 wt % firstcarbohydrate; about 89 wt % first carbohydrate; about 89.5 wt % firstcarbohydrate; about 90 wt % first carbohydrate; about 90.5 wt % firstcarbohydrate; about 91 wt % first carbohydrate; about 91.5 wt % firstcarbohydrate; about 92 wt % first carbohydrate; about 92.5 wt % firstcarbohydrate; about 93 wt % first carbohydrate; about 93.5 wt % firstcarbohydrate; about 94 wt % first carbohydrate; about 94.5 wt % firstcarbohydrate; about 95 wt % first carbohydrate; about 95.5 wt % firstcarbohydrate; about 96 wt % first carbohydrate; about 96.5 wt % firstcarbohydrate; about 97 wt % first carbohydrate; about 97.5 wt % firstcarbohydrate; about 98.5 wt % first carbohydrate; about 99 wt % firstcarbohydrate; or about 99.5 wt % first carbohydrate.

In some embodiments, a solid dispersion includes greater than 94 wt %first carbohydrate. In some embodiments, a solid dispersion includesgreater than 94.5 wt % first carbohydrate. In some embodiments, a soliddispersion includes greater than 95 wt % first carbohydrate. In someembodiments, a solid dispersion includes greater than 95.5 wt % firstcarbohydrate. In some embodiments, a solid dispersion includes greaterthan 96 wt % first carbohydrate. In some embodiments, a solid dispersionincludes greater than 96.5 wt % first carbohydrate. In some embodiments,a solid dispersion includes greater than 97 wt % first carbohydrate. Insome embodiments, a solid dispersion includes greater than 97.5 wt %first carbohydrate. In some embodiments, a solid dispersion includesgreater than 98 wt % first carbohydrate. In some embodiments, a soliddispersion includes greater than 98.5 wt % first carbohydrate. In someembodiments, a solid dispersion includes greater than 99 wt % firstcarbohydrate. In some embodiments, a solid dispersion includes greaterthan 99.5 wt % first carbohydrate.

In some embodiments, a solid dispersion includes about 0.5 wt % secondcarbohydrate; about 1 wt % second carbohydrate; about 1.5 wt % secondcarbohydrate; about 1.7 wt % second carbohydrate; about 2 wt % secondcarbohydrate; about 2.3 wt % second carbohydrate; about 2.5 wt % secondcarbohydrate; about 3 wt % second carbohydrate; about 3.5 wt % secondcarbohydrate; about 4 wt % second carbohydrate; about 4.5 wt % secondcarbohydrate; about 5 wt % second carbohydrate; about 5.5 wt % secondcarbohydrate; about 6 wt % second carbohydrate; about 6.5 wt % secondcarbohydrate; about 7 wt % second carbohydrate; about 7.5 wt % secondcarbohydrate; about 8 wt % second carbohydrate; about 8.5 wt % secondcarbohydrate; about 9 wt % second carbohydrate; about 9.5 wt % secondcarbohydrate; about 10 wt % second carbohydrate; about 10.5 wt % secondcarbohydrate; about 11 wt % second carbohydrate; about 11.5 wt % secondcarbohydrate; about 12 wt % second carbohydrate; about 12.5 wt % secondcarbohydrate; about 13 wt % second carbohydrate; about 13.5 wt % secondcarbohydrate; about 14 wt % second carbohydrate; about 14.5 wt % secondcarbohydrate; about 15 wt % second carbohydrate; about 15.5 wt % secondcarbohydrate; about 16 wt % second carbohydrate; about 16.5 wt % secondcarbohydrate; about 17 wt % second carbohydrate; about 17.5 wt % secondcarbohydrate; about 18.5 wt % second carbohydrate; about 19 wt % secondcarbohydrate; about 19.5 wt % second carbohydrate; or about 20 wt %second carbohydrate. In some embodiments, an excipient system includesabout 0.5 wt % third carbohydrate; about 1 wt % third carbohydrate;about 1.5 wt % third carbohydrate; about 1.7 wt % third carbohydrate;about 2 wt % third carbohydrate; about 2.3 wt % third carbohydrate;about 2.5 wt % third carbohydrate; about 3 wt % third carbohydrate;about 3.5 wt % third carbohydrate; about 4 wt % third carbohydrate;about 4.5 wt % third carbohydrate; about 5 wt % third carbohydrate;about 5.5 wt % third carbohydrate; about 6 wt % third carbohydrate;about 6.5 wt % third carbohydrate; about 7 wt % third carbohydrate;about 7.5 wt % third carbohydrate; about 8 wt % third carbohydrate;about 8.5 wt % third carbohydrate; about 9 wt % third carbohydrate;about 9.5 wt % third carbohydrate; about 10 wt % third carbohydrate;about 10.5 wt % third carbohydrate; about 11 wt % third carbohydrate;about 11.5 wt % third carbohydrate; about 12 wt % third carbohydrate;about 12.5 wt % third carbohydrate; about 13 wt % third carbohydrate;about 13.5 wt % third carbohydrate; about 14 wt % third carbohydrate;about 14.5 wt % third carbohydrate; about 15 wt % third carbohydrate;about 15.5 wt % third carbohydrate; about 16 wt % third carbohydrate;about 16.5 wt % third carbohydrate; about 17 wt % third carbohydrate;about 17.5 wt % third carbohydrate; about 18.5 wt % third carbohydrate;about 19 wt % third carbohydrate; about 19.5 wt % third carbohydrate; orabout 20 wt % third carbohydrate.

In some embodiments, a solid dispersion includes about 80 wt % to about99.5 wt % mannitol, about 0.5 wt % to about 20 wt % maltitol, and about0.5 wt % to about 20 wt % sorbitol. In some embodiments, a soliddispersion includes about 80 wt % mannitol; about 80.5 wt % mannitol;about 81 wt % mannitol; about 81.5 wt % mannitol; about 82 wt %mannitol; about 82.5 wt % mannitol; about 83 wt % mannitol; about 83.5wt % mannitol; about 84 wt % mannitol; about 84.5 wt % mannitol; about85 wt % mannitol; about 85.5 wt % mannitol; about 86 wt % mannitol;about 86.5 wt % mannitol; about 87 wt % mannitol; about 87.5 wt %mannitol; about 88 wt % mannitol; about 88.5 wt % mannitol; about 89 wt% mannitol; about 89.5 wt % mannitol; about 90 wt % mannitol; about 90.5wt % mannitol; about 91 wt % mannitol; about 91.5 wt % mannitol; about92 wt % mannitol; about 92.5 wt % mannitol; about 93 wt % mannitol;about 93.5 wt % mannitol; about 94 wt % mannitol; about 94.5 wt %mannitol; about 95 wt % mannitol; about 95.5 wt % mannitol; about 96 wt% mannitol; about 96.5 wt % mannitol; about 97 wt % mannitol; about 97.5wt % mannitol; about 98.5 wt % mannitol; about 99 wt % mannitol; orabout 99.5 wt % mannitol. In some embodiments, a solid dispersionincludes about 0.5 wt % maltitol; about 1 wt % maltitol; about 1.5 wt %maltitol; about 1.7 wt % maltitol; about 2 wt % maltitol; about 2.5 wt %maltitol; about 3 wt % maltitol; about 3.5 wt % maltitol; about 4 wt %maltitol; about 4.5 wt % maltitol; about 5 wt % maltitol; about 5.5 wt %maltitol; about 6 wt % maltitol; about 6.5 wt % maltitol; about 7 wt %maltitol; about 7.5 wt % maltitol; about 8 wt % maltitol; about 8.5 wt %maltitol; about 9 wt % maltitol; about 9.5 wt % maltitol; about 10 wt %maltitol; about 10.5 wt % maltitol; about 11 wt % maltitol; about 11.5wt % maltitol; about 12 wt % maltitol; about 12.5 wt % maltitol; about13 wt % maltitol; about 13.5 wt % maltitol; about 14 wt % maltitol;about 14.5 wt % maltitol; about 15 wt % maltitol; about 15.5 wt %maltitol; about 16 wt % maltitol; about 16.5 wt % maltitol; about 17 wt% maltitol; about 17.5 wt % maltitol; about 18.5 wt % maltitol; about 19wt % maltitol; about 19.5 wt % maltitol; or about 20 wt % maltitol. Insome embodiments, an excipient system includes about 0.5 wt % sorbitol;about 1 wt % sorbitol; about 1.5 wt % sorbitol; about 2 wt % sorbitol;about 2.3 wt % sorbitol; about 2.5 wt % sorbitol; about 3 wt % sorbitol;about 3.5 wt % sorbitol; about 4 wt % sorbitol; about 4.5 wt % sorbitol;about 5 wt % sorbitol; about 5.5 wt % sorbitol; about 6 wt % sorbitol;about 6.5 wt % sorbitol; about 7 wt % sorbitol; about 7.5 wt % sorbitol;about 8 wt % sorbitol; about 8.5 wt % sorbitol; about 9 wt % sorbitol;about 9.5 wt % sorbitol; about 10 wt % sorbitol; about 10.5 wt %sorbitol; about 11 wt % sorbitol; about 11.5 wt % sorbitol; about 12 wt% sorbitol; about 12.5 wt % sorbitol; about 13 wt % sorbitol; about 13.5wt % sorbitol; about 14 wt % sorbitol; about 14.5 wt % sorbitol; about15 wt % sorbitol; about 15.5 wt % sorbitol; about 16 wt % sorbitol;about 16.5 wt % sorbitol; about 17 wt % sorbitol; about 17.5 wt %sorbitol; about 18.5 wt % sorbitol; about 19 wt % sorbitol; about 19.5wt % sorbitol; or about 20 wt % sorbitol.

In some embodiments, a solid dispersion includes about 80 wt % to about99.5 wt % mannitol, about 0.5 wt % to about 20 wt % isomalt, and about0.5 wt % to about 20 wt % sorbitol. In some embodiments, a soliddispersion includes about 80 wt % mannitol; about 80.5 wt % mannitol;about 81 wt % mannitol; about 81.5 wt % mannitol; about 82 wt %mannitol; about 82.5 wt % mannitol; about 83 wt % mannitol; about 83.5wt % mannitol; about 84 wt % mannitol; about 84.5 wt % mannitol; about85 wt % mannitol; about 85.5 wt % mannitol; about 86 wt % mannitol;about 86.5 wt % mannitol; about 87 wt % mannitol; about 87.5 wt %mannitol; about 88 wt % mannitol; about 88.5 wt % mannitol; about 89 wt% mannitol; about 89.5 wt % mannitol; about 90 wt % mannitol; about 90.5wt % mannitol; about 91 wt % mannitol; about 91.5 wt % mannitol; about92 wt % mannitol; about 92.5 wt % mannitol; about 93 wt % mannitol;about 93.5 wt % mannitol; about 94 wt % mannitol; about 94.5 wt %mannitol; about 95 wt % mannitol; about 95.5 wt % mannitol; about 96 wt% mannitol; about 96.5 wt % mannitol; about 97 wt % mannitol; about 97.5wt % mannitol; about 98.5 wt % mannitol; about 99 wt % mannitol; orabout 99.5 wt % mannitol. In some embodiments, a solid dispersionincludes about 0.5 wt % isomalt; about 1 wt % isomalt; about 1.5 wt %isomalt; about 1.7 wt % isomalt; about 2 wt % isomalt; about 2.5 wt %isomalt; about 3 wt % isomalt; about 3.5 wt % isomalt; about 4 wt %isomalt; about 4.5 wt % isomalt; about 5 wt % isomalt; about 5.5 wt %isomalt; about 6 wt % isomalt; about 6.5 wt % isomalt; about 7 wt %isomalt; about 7.5 wt % isomalt; about 8 wt % isomalt; about 8.5 wt %isomalt; about 9 wt % isomalt; about 9.5 wt % isomalt; about 10 wt %isomalt; about 10.5 wt % isomalt; about 11 wt % isomalt; about 11.5 wt %isomalt; about 12 wt % isomalt; about 12.5 wt % isomalt; about 13 wt %isomalt; about 13.5 wt % isomalt; about 14 wt % isomalt; about 14.5 wt %isomalt; about 15 wt % isomalt; about 15.5 wt % isomalt; about 16 wt %isomalt; about 16.5 wt % isomalt; about 17 wt % isomalt; about 17.5 wt %isomalt; about 18.5 wt % isomalt; about 19 wt % isomalt; about 19.5 wt %isomalt; or about 20 wt % isomalt. In some embodiments, an excipientsystem includes about 0.5 wt % sorbitol; about 1 wt % sorbitol; about1.5 wt % sorbitol; about 2 wt % sorbitol; about 2.3 wt % sorbitol; about2.5 wt % sorbitol; about 3 wt % sorbitol; about 3.5 wt % sorbitol; about4 wt % sorbitol; about 4.5 wt % sorbitol; about 5 wt % sorbitol; about5.5 wt % sorbitol; about 6 wt % sorbitol; about 6.5 wt % sorbitol; about7 wt % sorbitol; about 7.5 wt % sorbitol; about 8 wt % sorbitol; about8.5 wt % sorbitol; about 9 wt % sorbitol; about 9.5 wt % sorbitol; about10 wt % sorbitol; about 10.5 wt % sorbitol; about 11 wt % sorbitol;about 11.5 wt % sorbitol; about 12 wt % sorbitol; about 12.5 wt %sorbitol; about 13 wt % sorbitol; about 13.5 wt % sorbitol; about 14 wt% sorbitol; about 14.5 wt % sorbitol; about 15 wt % sorbitol; about 15.5wt % sorbitol; about 16 wt % sorbitol; about 16.5 wt % sorbitol; about17 wt % sorbitol; about 17.5 wt % sorbitol; about 18.5 wt % sorbitol;about 19 wt % sorbitol; about 19.5 wt % sorbitol; or about 20 wt %sorbitol.

In some embodiments, a solid dispersion includes greater than 94 wt %mannitol. In some embodiments, a solid dispersion includes greater than95 wt % mannitol. In some embodiments, a solid dispersion includesgreater than 96 wt % mannitol. In some embodiments, a solid dispersionincludes greater than 97 wt % mannitol. In some embodiments, a soliddispersion includes greater than 98 wt % mannitol. In some embodiments,a solid dispersion includes greater than 99 wt % mannitol.

In some embodiments, a solid dispersion includes less than 5 wt %maltitol. In some embodiments, a solid dispersion includes less than 4wt % maltitol. In some embodiments, a solid dispersion includes lessthan 3 wt % maltitol. In some embodiments, a solid dispersion includesless than 2 wt % maltitol. In some embodiments, a solid dispersionincludes less than 1 wt % maltitol. In some embodiments, a soliddispersion includes less than 0.75 wt % maltitol. In some embodiments, asolid dispersion includes less than 0.50 wt % maltitol. In someembodiments, a solid dispersion includes less than 0.25 wt % ofmaltitol.

In some embodiments, a solid dispersion includes less than 5 wt %isomalt. In some embodiments, a solid dispersion includes less than 4 wt% isomalt. In some embodiments, a solid dispersion includes less than 3wt % isomalt. In some embodiments, a solid dispersion includes less than2 wt % isomalt. In some embodiments, a solid dispersion includes lessthan 1 wt % isomalt.

In some embodiments, a solid dispersion includes less than 5 wt %lactitol. In some embodiments, a solid dispersion includes less than 4wt % lactitol. In some embodiments, a solid dispersion includes lessthan 3 wt % lactitol. In some embodiments, a solid dispersion includesless than 2 wt % lactitol. In some embodiments, a solid dispersionincludes less than 1 wt % lactitol. In some embodiments, a soliddispersion includes less than 0.75 wt % lactitol. In some embodiments, asolid dispersion includes less than 0.50 wt % lactitol. In someembodiments, a solid dispersion includes less than 0.25 wt % oflactitol.

In some embodiments, a solid dispersion includes less than 5 wt %sorbitol. In some embodiments, a solid dispersion includes less than 4wt % sorbitol. In some embodiments, a solid dispersion includes lessthan 3 wt % sorbitol. In some embodiments, a solid dispersion includesless than 2 wt % sorbitol. In some embodiments, a solid dispersionincludes less than 1 wt % sorbitol. In some embodiments, a soliddispersion includes less than 0.75 wt % sorbitol. In some embodiments, asolid dispersion includes less than 0.50 wt % sorbitol. In someembodiments, a solid dispersion includes less than 0.25 wt % ofsorbitol.

In some embodiments, a solid dispersion includes greater than 90 wt %mannitol and two polyols. In some embodiments, a solid dispersionincludes greater than 91 wt % mannitol and two polyols. In someembodiments, a solid dispersion includes greater than 92 wt % mannitoland two polyols. In some embodiments, a solid dispersion includesgreater than 93 wt % mannitol and two polyols. In some embodiments, asolid dispersion includes greater than 94 wt % mannitol and two polyols.In some embodiments, a solid dispersion includes greater than 95 wt %mannitol and two polyols. In some embodiments, a solid dispersionincludes greater than 96 wt % mannitol and two polyols. In someembodiments, a solid dispersion includes greater than 97 wt % mannitoland two polyols. In some embodiments, a solid dispersion includesgreater than 98 wt % mannitol and two polyols. In some embodiments, asolid dispersion includes greater than 99 wt % mannitol and two polyols.

In some embodiments, a solid dispersion includes less than 5 wt %sorbitol and two polyols. In some embodiments, a solid dispersionincludes less than 4 wt % sorbitol and two polyols. In some embodiments,a solid dispersion includes less than 3 wt % sorbitol and two polyols.In some embodiments, a solid dispersion includes less than 2 wt %sorbitol and two polyols. In some embodiments, a solid dispersionincludes less than 1 wt % sorbitol and two polyols. In some embodiments,a solid dispersion includes less than 0.75 wt % sorbitol and twopolyols. In some embodiments, a solid dispersion includes less than 0.50wt % sorbitol and two polyols. In some embodiments, a solid dispersionincludes less than 0.25 wt % sorbitol and two polyols.

In some embodiments, a solid dispersion includes less than 5 wt %maltitol and two polyols. In some embodiments, a solid dispersionincludes less than 4 wt % maltitol and two polyols. In some embodiments,a solid dispersion includes less than 3 wt % maltitol and two polyols.In some embodiments, a solid dispersion includes less than 2 wt %maltitol and two polyols. In some embodiments, a solid dispersionincludes less than 1 wt % maltitol and two polyols. In some embodiments,a solid dispersion includes less than 0.75 wt % maltitol and twopolyols. In some embodiments, a solid dispersion includes less than 0.50wt % maltitol and two polyols. In some embodiments, a solid dispersionincludes less than 0.25 wt % maltitol and two polyols.

Methods of Making

Any suitable process may be used to manufacture a solid dispersion of atleast two or at least three carbohydrates, including but not limited tospray drying, fluid bed, co-granulation or high shear mixing.

Co-Spray Dried

In some embodiments, the solid dispersion of at least two or at leastthree carbohydrates are co-spray dried. A suitable method of co-spraydrying is described in U.S. Pat. No. 7,118,765, which is incorporated byreference herein in its entirety. Any spray dryer may be useful in thepresent invention. In some embodiments of the invention, an S1 SprayFluid Bed Dryer with a 2.1 meter diameter is used (DRYTEC; Tonbridge,Kent, ENGLAND). The spray dryer operates by atomizing a liquid feedmaterial in a stream of air or other gas. The main use of the spraydrying equipment is drying but the equipment can also be used foragglomerating, congealing, encapsulation, cooling and/or conditioningthe composition of the present invention. A flow diagram depicting theoperation pattern of the fluid bed spray dryer is shown in FIG. 1 .

Air for drying is heated by a heater 1 and enters the top of a dryingchamber 4 through a hot air duct 8. A feed pump 2 delivers the liquidfeed through feed line 3 to an atomizer which sprays the composition infine droplets into a hot air stream entering the top of a drying chamber4. This causes rapid drying due to the large liquid area exposed. In thepresent invention, one of several atomizers can be used. For example, acentrifugal driven atomizer, a two fluid nozzle using a jet ofcompressed air to atomize the feed, or a pressure nozzle atomizer can beused in the present invention.

An integrated fluid bed 10 is attached at the bottom of chamber 4. Thefines and air leave from a side outlet 9 of the cone of drying chamber 4to a cyclone 5. Cyclone 5 separates the fines from the air. The air isexhausted out through a bag filter 6. The fines are recycled to the topof drying chamber 4 into a wet zone 11 where agglomeration takes place,and drop into integrated fluid bed 10. The action of the fluidization bythe hot air supplied to the fluid bed allows the coarser particles todry further and the fines are taken away to cyclone 5.

The carbohydrate solution (for example, at least two polyols or at leastthree polyols) is then fed into the integrated spray fluid bed dryingchamber unit under sealed conditions and a controlled stream of hot airat a temperature of about 200 degrees Celsius (° C.) dries the solutionin the form of fine droplets. Once the desired particle size isachieved, the carbohydrate product is collected. Particle size can rangefrom about 0.1 to 500 microns. In one embodiment of the presentinvention, at least 85% of the particles are about 100 microns orgreater. In another embodiment of the present invention, at least 50% ofthe particles are about 100 microns or greater. The smaller particles(“fines”) generated during this process are recycled back to the top ofdrying chamber 4 for further agglomeration.

In one embodiment, a spray dried mixture of 92% mannitol/8% maltitol wasprepare on an Anhydro Micra—35 using an inlet temperature of 195 ° C.,an outlet temp of 90 to 95° C., air flow of 32 kg/hr, a gas pressuredrop of 2.6 psig, an atomization air flow at 4.1 kg/hr, an atomizationair temperature of 60° C., an atomization air pressure of 39 psig, achamber jacket temperature at 90° C., and a cyclone jacket surfacetemperature of 90° C. The spray rate of liquid was adjusted to maintaina 90° C. outlet temperature.

Co-Granulation

In some embodiments of the invention, a carbohydrate mixture of at leasttwo or at least three carbohydrates is prepared by co-granulation.

Fluid Bed

In some embodiments, a solid dispersion of at least two or at leastthree carbohydrates is prepared with a fluid bed. In one example, amannitol, maltitol, and sorbitol mixture may be prepared by adding 20 kgof milled 30 μm or smaller mannitol Vwm diameter powder (such as Getec,Roquette, etc) to a fluid bed (such as Fluid Air Model 50 L). A solutionis made from 170 g maltitol and 80 g mannitol in 500 mL of water(solution A). A solution is also made from 170 g maltitol, 320 gmannitol, and 460 g of sorbitol in 2000 mL of water. (Solution B). Withan inlet temperature of 80° C., mannitol powder bed is heated to 30° C.,with an air volume of 140 SCFM. Then, Solution A may be sprayed on at arate of 70 g/min, followed by Solution B at 70 to 150 g/min to obtainagglomerates. The product may then be dried at 80° C. and 140 SCFM untilthe product is less than 0.5% moisture.

High Shear

In some embodiments, a solid dispersion of at least two or at leastthree carbohydrates is prepared using high shear. In one example, amixture of mannitol, maltitol, and sorbitol can be prepared by adding 20kg of milled 30 μm or smaller mannitol Vwm diameter powder (such asGetec, Roquette, etc) and 170 g maltitol to a horizontal high shearmixer (such as Littleford 5 cu ft mixer—JH Day Cincinati Ohio). In someembodiments, solution is made from 170 g maltitol, 160 g mannitol, and460 g sorbitol in 1000 mL water. The solution can then be added to thehigh shear mixer to granulate particles. If necessary, additional liquidmay be added to obtain the size particles desired. Next, the particlescan be dried at 80° C. and 140 SCFM in a fluid bed (such as Fluid AirModel 50L) until product is less than 0.5% moisture. The product canthen be milled and screened to the appropriate particle size ifnecessary using, for example, a FitzMill Model D6 (Fitzpatrick Company)at 2000 RPM, and a screen and a Sweco screener using, for example, a USS20 mesh screen.

Characteristics

In some embodiments, solid dispersions and/or excipient systemsincluding at least two carbohydrates, such as mannitol and maltitol orisomalt, or at least three carbohydrates, such as mannitol, maltitol orisomalt, and sorbitol, demonstrate superior functionality such astabletability, durability, organoleptic characteristics, disintegrationtime, and/or an advantageous decrease in sensitivity to the amount ofcompaction. For example, in some embodiments, an increased compactionpressure applied to the solid dispersion or excipient system results ina tablet with a more favorable friability value, increased hardnessvalues, and surprisingly, only a slight increase in disintegration time.Such characteristics may be displayed for solid dispersions or excipientsystems including co-granulated and/or spray dried carbohydrates.

In some embodiments, an excipient system including 90 wt % mannitol and10 wt % maltitol has a hardness value of about 14 kP upon application ofa 15 kN compression force. Such excipient system may have a friabilityvalue of about 0.20%. Such excipient system may have a disintegrationtime of less than about 10 minutes

In some embodiments, an excipient system including 90 wt % mannitol and10 wt % maltitol has a hardness value of about 32 kP upon application ofa 30 kN compression force. Such excipient system may have a friabilityvalue of about 0.08%. Such excipient system may have a disintegrationtime of less than about 10 minutes.

In some embodiments, an excipient system including 99 wt % mannitol and1 wt % maltitol has a hardness value of about 16 kP upon application ofa 15 kN compression force. Such excipient system may have a friabilityvalue of about 0.14%. Such excipient system may have a disintegrationtime of less than about 8 minutes.

In some embodiments, an excipient system including 99 wt % mannitol and1 wt % maltitol has a hardness value of about 22 kP upon application ofa 30 kN compression force. Such excipient system may have a friabilityvalue of about 0.18%. Such excipient system may have a disintegrationtime of less than about 8 minutes.

In some embodiments, an excipient system including 96.5 wt % mannitoland 3.5 wt % maltitol has a hardness value of about 14 kP uponapplication of a 15 kN compression force. Such an excipient system mayhave a friability value of about 0.22%. Such an excipient system mayhave a disintegration time of less than about 6 minutes.

In some embodiments, an excipient system including 96.5 wt % mannitoland 3.5 wt % maltitol has a hardness value of about 28 kP uponapplication of a 30 kN compression force. Such an excipient system mayhave a friability value of about 0.22%. Such an excipient system mayhave a disintegration time of less than about 8 minutes.

In some embodiments, an excipient system including 96 wt % mannitol, 1.7wt % maltitol, and 2.3 wt % sorbitol has a hardness value of about 22 kPupon application of a 13 kN compression force. Such an excipient systemmay have a friability value of about 0.11%.

In some embodiments, an excipient system including 96 wt % mannitol, 1.7wt % maltitol and 2.3 wt % sorbitol has a hardness value of about 50 kPupon application of a 33 kN compression force. Such an excipient systemmay have a friability value of about 0.13%.

In some embodiments, an excipient system including 91.2 wt % mannitol,6.5 wt % maltitol and 2.3 wt % sorbitol has a hardness value of about 18kP upon application of a 13 kN compression force. Such an excipientsystem may have a friability value of about 0.20%.

In some embodiments, an excipient system including 91.2 wt % mannitol,6.5 wt % maltitol and 2.3 wt % sorbitol has a hardness value of about 35kP upon application of a 33 kN compression force. Such an excipientsystem may have a friability value of about 0.24%.

In some embodiments, an excipient system including 91.2 wt % mannitol,2.3% sorbitol and 6.5 wt % maltitol has a hardness value of about 14 kPupon application of a 13 kN compression force. Such an excipient systemmay have a friability value of about 0.17%.

In some embodiments, an excipient system including 91.2 wt % mannitol,2.3% sorbitol and 6.5 wt % maltitol has a hardness value of about 45 kPupon application of a 34 kN compression force. Such an excipient systemmay have a friability value of about 0.13%.

In some embodiments, the moisture content of the solid dispersion may beless than about 8%, less than about 5%, less than about 3%, less thanabout 2%, less than about 1% or less than about 0.5%. In one embodimentof the present invention, the moisture content of the solid dispersionis about 0.3%.

In some embodiments, the friability of the solid dispersion in powderform is about 15% to about 35%. In some embodiments, the friability ofthe solid dispersion in powder form is less than 35%, less than 30%,less than 25%, or less than 20%.

In some embodiments, the friability of the resulting compressed soliddispersion may be less than about 5%, less than about 4%, less thanabout 3%, less than about 2%, less than about 1%, less than about 0.5%,less than about 0.4%, less than about 0.3%, less than about 0.2%, orless than about 0.1%.

In some embodiments, the compactability of the resulting compressedsolid dispersion may exhibit a hardness from about 15 kP to about 50 kPwhen a compression force of about 13 kN to about 35 kN is applied. Inone embodiment, the compactability of the resulting compressed soliddispersion may exhibit a hardness from about 15 kP to about 35 kP when acompression force of about 13 kN to about 35 kN is applied. In oneembodiment, the compactability of the resulting compressed soliddispersion may exhibit a hardness from about 22 kP to about 50 kP when acompression force of about 13 kN to about 35 kN is applied. In oneembodiment, the compactability of the resulting compressed soliddispersion may exhibit a hardness greater than 15 kP at a compressionforce of 13 kN. In one embodiment, the compactability of the resultingcompressed solid dispersion may exhibit a hardness greater than 35 kP ata compression force of 35 kN.

In one embodiment, the durability of the resulting compressed soliddispersion may exhibit a friability of 0.5% or less when a compressionforce of about 13 kN to about 35 kN is applied.

In one embodiment, solid dispersions of the present invention include atleast two carbohydrates with different solubilities, wherein the soliddispersion has a microcrystalline plate structure. In one embodiment,solid dispersions of the present invention include at least twocarbohydrates with different concentrations, wherein the soliddispersion has a microcrystalline plate structure.

In one embodiment, the crystalline layers of the microcrystalline platestructure have a thickness of less than 5 microns, preferably less than3 microns and most preferably less than 1 micron. In one embodiment, thecrystalline layers of the microcrystalline plate structure have athickness of about 0.5 microns to about 5 microns. In one embodiment,the crystalline layers of the microcrystalline plate structure have athickness of about 0.5 microns to about 2 microns. In one embodiment,the crystalline layers of the microcrystalline plate structure are incontact with one another. In some embodiments, the small size of thecrystalline layers adds to a creamy mouth feel upon disintegration.

In one embodiment a solid dispersion with a microcrystalline platestructure is achieved by selecting carbohydrates with differentsolubilities and making a solution within a range of percent ofsaturation of the different carbohydrate components at a given solutionprocess temperature. Percent of saturation is defined as (componentconcentrations at process temperature)/(saturation of the component atthe process temperature)*100. Temperatures ranging from 40° C. to 99° C.can be used for the solution process temperature. The sequence ofco-crystallization that forms the microcrystalline plate structure ispredicated on % of saturation of the components in the solution.

In one embodiment, the core carbohydrate component is processed at about60% to about 99.5% of its saturation concentration, any transitioncomponent(s) added at less than about 1% to about 59.5%, and the surfacecomponent added at less than about 0.5% to about 40%.

In a more preferred embodiment, the core carbohydrate component isprocessed at about 75% to about 99.5% of its saturation concentration,any transition component(s) added at less than about 1% to about 24.5%,and the surface component added at less than about 0.5% to about 25%.

In an even more preferred embodiment, the core carbohydrate component isprocessed at about 85% to about 99.5% of its saturation concentration,any transition component(s) is added at less than about 1% to about14.5%, and the surface component is added at greater than about 0.5% toabout 15%.

In a most preferred embodiment, the core carbohydrate component isprocessed at about 95% to about 99.5% of its saturation concentration,any transition component is added at greater than about 1% to about4.5%, and the surface component is added at greater than about 0.5% toabout 5%.

While not wishing to be bound by theory, it is speculated thatinteraction between the co-processed carbohydrates may be substantiallyresponsible for the surprising characteristics of the solid dispersionsof some embodiments of the invention.

In one embodiment, a solid dispersion of the present invention comprisesthree zones: a core, a transition and a surface. Zone one is a firstcarbohydrate crystal core. Zone two, the transition layer, can be one ormultiple layers in which a single dispersed material or multipledispersed materials are co-crystallized with first carbohydrate. Thetransition dispersed material serves to segment and plasticize thetransition zone. There are two factors that affect the transition; oneis the solubility of the dispersed phase in water at the processtemperature. (See Table 1 for solubility of various carbohydrates.) Thelower soluble dispersed material at the same temperature willco-crystallize later than higher soluble materials. The other factor isthe concentration of the dispersed material in solution. The higher theconcentration the earlier in the process it will co-crystallize. Thuscore thickness and transition zone thickness can be adjusted to getco-crystallization and a thinner core early in process and by adjustingeither the solubility of the dispersed material or lowering theconcentration-of the dispersed material. Zone three, the surface zone,incorporates carbohydrates for surface placement. The surface is createdas a composition of multiple carbohydrates with a reducing surfacebonding energy.

TABLE 1 Carbohydrate Solubilities Melt Solubility Mole Point At 25(g/100 g Raw Material Wt ° C. H₂O) Sorbitol 182  99-101 235 g Mannitol182 165-169 22 g HSH HP+ N/a Soluble Maltitol Solution N/a SolubleMaltitol 344 144-147 175 g Xylitol 152.17 92-95 200 g LactitolMonohydrate 362.33  95-101 140 g Anhydrous Isomalt 344.32 145-150 39 gErythritol 122 119-123 61 g Glycerin 99 17.8 Soluble Polydextrose<22,000 130   80 g Sucrose 342 160-186 185 g Fructose 180 102-105 400 gMaltose 342 120-125 70 g

The use of differential solubility (Percent of saturation) as a means ofcontrolling the microcrystalline plate structure is based on the amountof water remaining in the solid dispersion droplet. Percent ofsaturation of the first carbohydrate is closest to 100% causing it tocrystallize first. As evaporation process continues, the amount of waterremaining is lowered to saturation conditions for the next percent ofsaturation dispersant. Thus co-crystallization occurs of each of theremaining dispersed materials in a planned order. Both cooling andevaporation can cause crystallization. As the process can be setup to beisothermal in a narrow range, the cooling of the particles especially inspray drying is considered negligible. In the following example in Table2, the solution temperature is 80° C. and the exiting dried product fromthe spray drier is 85 to 95° C. The droplet cooling is thus limited.

The calculation for evaporation involves calculation of the amount ofwater remaining to maintain solubility of each material as the processof evaporation continues. Table 2 below shows the solubility at 80° C.,the spray liquid temperature. By subtraction from 100, the amount ofwater needed to be at saturation is calculated in column 2. The selectedconcentrations of materials are placed into water in this case, 55 kilosof water. Note mannitol crystallizes after 8.84% of the water hasevaporated, followed by maltitol co-crystallizing with mannitol at99.65% water evaporated or 0.35% water remaining and then by sorbitolco-crystallizing at 99.83% evaporated or 0.17% of water remaining. Thecalculation uses a ratio of (amount of water at saturation)/(amount ofcarbohydrate at saturation) as a ratio multiplied by the amount ofcarbohydrate in batch to determine the amount of water at saturation.For example, (8/92*1.08)=0.0.09375 for sorbitol. The sequence ofsaturation and the amount of material coming out of solution thus is thedetermining factor for core, transition and surface compositionthickness and composition. Materials selected for inclusion are selectedas those that will form a solid dispersion as defined herein.

First crystallization can be a crystalline or co-crystallizationmaterial as a core and the transition to the surface can be the sameco-crystallization and thus a two carbohydrate system. First, tocrystallize, the dispersant phase can be from about 0.5% to about 99.5%of the total mass with a 0% to 99.5% transition zone and 0.5 to 99.5%surface zone.

A solution of three or more carbohydrates with different solubilities isprepared. In order to co-crystallize the carbohydrates into a soliddispersion with a microplate structure, this solution is first processedto approximately 100 percent saturation or more of the carbohydrate withthe highest percent saturation in the solution.

The sequence of crystallization/co-crystallization of three or morecarbohydrates occurs due to either solvent loss, temperature change ofthe solution or both. The microplate structure is dictated by the %saturation of carbohydrates selected in preparing the liquid solution tobe processed. The process of co-crystallization can be accomplished byspraying the close to ˜100% saturation liquid into a fluid bed or spraydrier or spraying a nucleated suspension (containing smallmicrocrystals) into a fluid bed or spray drier. Process temperature canbe designed for conditions to dry at 40° C. to 210° C. inlettemperatures.

TABLE 2 Carbohydrate Saturations 80° C. Kilos % of % of Solubility waterat water water Kilos/100 Kilos of saturation remaining dried Kilo waterat % in (55 kilos at off at solution saturation Formulation total)saturation saturation Sorbitol 92 8 1.08 0.09375 0.17% 99.83% Maltitol80.5 19.5 0.8 0.193032 0.35% 99.65% Mannitol 47.3 52.7 45 50.1374291.16% 8.84% Isomalt 71 29.0 Lactitol 82 18.0

Coated Carbohydrate

In some embodiments, a solid dispersion and/or excipient system includesa coated carbohydrate and/or a coated carbohydrate mixture. In someembodiments, a solid dispersion and/or excipient system includes acoated polyol and/or coated polyol mixture. In some embodiments, anexcipient system includes a coated sugar and/or coated sugar mixture. Insome embodiments, a solid dispersion is coated.

Components

In some embodiments, a solid dispersion and/or excipient system includesa coated polyol, such as mannitol, or coated polyol mixture. In someembodiments, mannitol may be prepared by spray drying, such as Mannogem™EZ (SPI Pharma, Inc., Wilmington, Del.) spray dried mannitol. In someembodiments, spray dried mannitol is prepared with a spray drier such asthe Buchi Mini-Spray Drier, Model B290. In one embodiment, spray driedmannitol is prepared on the Buchi Model B290 using a 0.7 mm nozzle tip,200° C. inlet temperature, 90-97° C. outlet temperature maintained byspray rate, an air flow of 15 mL/min, and a 45% mannitol solution at an80° C. minimum temperature. Mannitol may also be prepared by othersuitable methods. Carbohydrates and carbohydrate mixtures such aspolyols and polyol mixtures may be prepared by any suitable method, suchas, spray drying, fluid bed, co-granulation or high shear mixing asdescribed in the Carbohydrate Mixture sections above.

In some embodiments, suitable coatings may include, but are not limitedto, soluble polymer materials. Suitable coatings may include, but arenot limited to, polyvinylpyrrolidones, polyvinylalcohols, polyethylenegraft copolymers, polyethylene glycols, ethylene glycol/propylene glycolgraft coplomers, hydroxypropylmethylcellulose, hydroxypropylcelluose,hydroxyethylcellulose, carrageenans, pectins, xantans and alginates. Insome embodiments, a suitable coating includes 60:40 copolymer ofvinylpyrrolidone and vinyl acetate (i.e., copovidone) such as Plasdone®S630 (International Specialty Products). In some embodiments, a soliddispersion and/or excipient system includes a coating in an amount ofabout 0.1 wt % to about 5 wt %; about 0.2 wt % to about 4 wt %; about0.3 wt % to about 3 wt %; about 0.4 wt % to about 2 wt %; or about 0.5wt % to about 1 wt %. In some embodiments, a solid dispersion and/orexcipient system includes a coating in amount of about 0.1 wt %; about0.2 wt %; about 0.3 wt %; about 0.4 wt %; about 0.5 wt %; about 0.6 wt%; about 0.7 wt %; about 0.8 wt %; about 0.9 wt %; about 1 wt %; about1.1 wt %; about 1.2 wt %; about 1.3 wt %; about 1.4 wt %; about 1.5 wt%; about 1.6 wt %; about 1.7 wt %; about 1.8 wt %; about 1.9 wt %; about2 wt %; about 3 wt %; about 4 wt %; or about 5 wt %.

Methods of Making

Any suitable method may be used to prepare a coated carbohydrate and/orcoated carbohydrate mixture.

Fluid Bed

In some embodiments, a coated carbohydrate, such as a polyol or sugar,or coated carbohydrate mixture, such as a polyol mixture or sugarmixture, is prepared using a fluid bed. In one example, mannitol coatedwith copovidone can be made as follows:

Ingredient List: DESCRIPTION QTY (kg) Supplier Mannitol (Mannogem EZUSP/EP) 396.0 SPI Pharma Copovidone (Plasdone S-630) 4 ISP Corp Total400

Using, a Fluid Air 1000 fluid bed dryer GRANULATOR, Mannogem EZ ischarged into the fluid bed. The product temperature is allowed to reachat least 30° C. prior to spraying the solution. The solution is 4 kg ofS-630 in 29 kg of water, and is made by adding the Plasdone S-630 slowlyto a stirring of the solution.

The spraying process parameters include 2000-4000 SCFM (target: 2800SCFM), inlet air temperature of 75-100° C., and a solution spray rate of0.5-2.0 kg/min. The approximate operating time is 30 minutes ofspraying. Once the spraying of the solution is complete, the batch maybe dried according to the following parameters: product temperature of30-40° C. (target 35° C.) and air flow of 1000-3000 SCFM. When theoutlet temperature reaches approximately 35° C., a sample may be pulledand tested for moisture via a standard lod test. If the target moisturelevel of less than or equal to 1.0% is not reached, the batch may becooled.

High Shear

In some embodiments, a coated carbohydrate, such as a polyol or sugar,or coated carbohydrate mixture, such as a polyol mixture or sugarmixture, is prepared using high shear. In one example, mannitol coatedwith copovidone is prepared by first adding 20 kg of mannitol (such asMannogem EZ) and 60 g of Plasdone S-630 (PV/VA copolymer) using a highshear mixer, such as Littleford Lodige 5 cu ft high shear granulator (JHDAY, Cincinnati, Ohio). A solution is made of 12% Plasdone S-630 inwater using 140 g copovidone and 210 g of mannitol per 1173 mL of water.With the mixer ploughs running at 60 RPM, the copovidone solution isslowly sprayed. The product can then be dried in a fluid bed, such asFluid Air Model 50 L (Fluid Air Corp, Aurora, Ill.), at an inlettemperature of 60° C. and air flow of 150 SCFM until the productcontains less than 0.5% moisture.

Characteristics

In some embodiments, a solid dispersion and/or excipient systemincluding a coated carbohydrate, such as a polyol or sugar, or coatedcarbohydrate mixture, such as a polyol mixture or sugar mixture,exhibits superior functionality such as tabletability, organolepticcharacteristics, and faster disintegration times. Excipient systemsincluding a coated carbohydrate, such as a polyol or sugar, or coatedcarbohydrate mixture, such as a polyol mixture or sugar mixture, mayrapidly develop a thin smooth liquid suspension in the mouth ondisintegration (creamy mouth feel) at about 1% or less concentration ofwater soluble polymer without effecting the overall disintegration timeof the tablet made from this composition. In some embodiments, in orallydisintegrating tablets, the creamy mouth feel suspension developed helpshide large particle APIs, and reduces an unpleasant feeling ofgrittiness as suspension particles are thin microplates and dissolvable.In some embodiments, an excipient system including a coatedcarbohydrate, such as a polyol or sugar, or coated carbohydrate mixture,such as a polyol mixture or sugar mixture, exhibits low friability evenat the lower compression forces.

Combination Excipient System

In some embodiments, an excipient system includes (1) a solid dispersionof at least two carbohydrates and (2) a coated carbohydrate orcarbohydrate mixture. In some embodiments, an excipient system includes(1) a solid dispersion of at least three carbohydrates and (2) a coatedcarbohydrate and/or coated carbohydrate mixture.

Components

In some embodiments, an excipient system includes a mixture of at leasttwo carbohydrates, such as polyols and/or sugars. A suitablecarbohydrate mixture may include, for example, mannitol and maltitol. Insome embodiments, an excipient system includes a mixture of at leastthree carbohydrates, such as polyols and/or sugars. A suitablecarbohydrate mixture may include, for example, mannitol, maltitol, andsorbitol. The carbohydrates may be co-spray dried or co-granulated, asdescribed above. In some embodiments, an excipient system includesmannitol and maltitol in the relative amounts described above. In someembodiments, an excipient system includes about 30 wt % to about 70 wt %polyol mixture; about 40 wt % to about 60 wt % polyol mixture; about 45wt % to about 55 wt % polyol mixture; about 47 wt % to about 53 wt %polyol mixture; or about 50 wt % polyol mixture.

In some embodiments, an excipient system includes a coated carbohydrate,such as a polyol or sugar, or coated carbohydrate mixture, such as apolyol mixture or sugar mixture, as described above. An excipient systemmay include about 1 wt % to about 40 wt % coated carbohydrate orcarbohydrate mixture; about 5 wt % to about 35 wt % coated carbohydrateor carbohydrate mixture; about 10 wt % to about 30 wt % coatedcarbohydrate or carbohydrate mixture; about 15 wt % to about 25 wt %coated carbohydrate or carbohydrate mixture; about 17 wt % to about 23wt % coated carbohydrate or carbohydrate mixture; or about 20 wt %coated carbohydrate or carbohydrate mixture.

Methods of Making

In some embodiments the components described above are admixed. Themixture may then be compressed to tablet form by known methods with orwithout a coated or uncoated or modified Active PharmaceuticalIngredient (API).

Characteristics

In some embodiments, an excipient system including a carbohydratemixture as described herein and a coated carbohydrate or carbohydratemixture (e.g., at least one spray dried polyol coated with a solublepolymer material), as described above, demonstrates superiorfunctionality such as tabletability, durability, organolepticcharacteristics, faster disintegration time, and/or an advantageousdecrease in sensitivity to the compaction pressure. For example, in someembodiments, an increased compaction pressure results in a tabletdisplaying a more favorable friability value, increased hardness values,and surprisingly, only a slight or no increase in disintegration time.

Additionally, lower compaction pressures may be required to achieve atablet with acceptable hardness and friability values. In someembodiments, an excipient system including a coated carbohydrate orcarbohydrate mixture and a carbohydrate mixture exhibits low friabilityeven at the lower compression forces. These properties may be useful formaintaining taste-masking or controlled release properties of APIsduring compaction by avoiding rupture of such components as the tastemask coating or a modified active. In some embodiments, actives aremodified to decrease unpleasant taste, control its release, increasebioavailability by improving solubility and/or permeation, or tostabilize the API. In some embodiments, such modifications preventrupture of the bioenhancement coating or fracture of the bioenhanced APIstructure. Being able to form tablets at lower forces may allow for thisstructure to remain more intact during the tablet process and maydeliver the API more effectively to the patient. Increasedcompactability at lower compression forces also reduces tablet press andpunch wear.

In some embodiments, an excipient system including a carbohydratemixture and a coated carbohydrate or carbohydrate mixture exhibitssuperior functionality such as organoleptic characteristics. Excipientsystems including a carbohydrate mixture and a coated carbohydrate orcarbohydrate mixture may rapidly develop a thick, smooth liquid in themouth on disintegration (creamy mouth feel) at about 1% or lessconcentration of water soluble polymer without effecting the overalldisintegration time of the tablet. In some embodiments, such superiororganoleptic functionality helps hide large particle coated or uncoatedAPIs, and reduces the feeling of grittiness.

In some embodiments, an excipient system including a carbohydratemixture and a coated carbohydrate or carbohydrate mixture exhibitssuperior dilution potential. In some embodiments, an excipient systemincluding a carbohydrate mixture and a coated carbohydrate orcarbohydrate mixture retains its functionality even after dilution withanother material such as an API or disintegrant. In some embodiments, anexcipient system may be highly compactable, accommodating a high dose ofAPI and thereby facilitating creation of a more robust tablet. In someembodiments, an excipient system including a carbohydrate mixture and acoated carbohydrate or carbohydrate mixture is highly compactable, asapplication of a low compression force results in a tablet with moderateto high hardness levels.

Additional Components for Excipient Systems

The excipient systems listed above may include a number of additionalcomponents.

In some embodiments, an excipient system includes a polyol. A suitablepolyol may include mannitol, such as Mannogem™ EZ (SPI Pharma, Inc.,Wilmington, Del.) spray dried mannitol. In some embodiments, anexcipient system includes about 1 wt % to about 30 wt % polyol; about 5wt % to about 25 wt % polyol, about 10 wt % to about 20 wt % polyol;about 12 wt % to about 18 wt % polyol; or about 15 wt % polyol.

In some embodiments, an excipient system includes a disintegrant.Suitable disintegrants include but are not limited to crospovidone (e.g.Plasdone® XL, Kollidone®, Polyplasdone®), alginic acid, croscarmellosesodium (e.g. Ac-Di-Sol®, Primellose®), guar gum, microcrystallinecellulose, polacrilin potassium, powdered cellulose, sodium alginate,and sodium starch glycolate (e.g. Explotab®). In some embodiments, anexcipient system includes about 1 wt % to about 30 wt % disintegrant;about 5 wt % to about 25 wt % disintegrant; about 10 wt % to about 20 wt% disintegrant; about 12 wt % to about 18 wt % disintegrant; or about 15wt % disintegrant.

Additional suitable components may also be included in an excipientsystem of the present invention at amounts appropriate to achieve thedesired properties.

In some embodiments, an excipient system includes a mixture of at leasttwo carbohydrates and a disintegrant. In some embodiments, an excipientsystem includes a mixture of at least two polyols, such as mannitol andmaltitol, and a disintegrant. In some embodiments, an excipient systemincludes a mixture at least three carbohydrates and a disintegrant. Insome embodiments, an excipient system includes a mixture at least threepolyols, such as mannitol, maltitol, and sorbitol, and a disintegrant.

In some embodiments, an excipient system includes a mixture at least twocarbohydrates, a disintegrant, and a carbohydrate. In some embodiments,an excipient system includes a mixture at least two polyols, such asmannitol and maltitol, a disintegrant, and a polyol. In someembodiments, an excipient system includes a mixture of at least threecarbohydrates, a disintegrant, and a carbohydrate. In some embodiments,an excipient system includes a mixture of at least three polyols, suchas mannitol, maltitol, and sorbitol, a disintegrant, and a polyol.

In some embodiments, an excipient system includes a mixture at least twocarbohydrates, a disintegrant, and a coated carbohydrate. In someembodiments, an excipient system includes a mixture at least twopolyols, such as mannitol and maltitol, a disintegrant, and a coatedpolyol. In some embodiments, an excipient system includes a mixture ofat least three carbohydrates, a disintegrant, and a coated carbohydrate.In some embodiments, an excipient system includes a mixture of at leastthree polyols, such as mannitol, maltitol, and sorbitol, a disintegrant,and a coated polyol.

In some embodiments, an excipient system includes a mixture at least twocarbohydrates, a disintegrant, a carbohydrate, and a coatedcarbohydrate. In some embodiments, an excipient system includes amixture at least two polyols, such as mannitol and maltitol, adisintegrant, a polyol, and a coated polyol. In some embodiments, anexcipient system includes a mixture of at least three carbohydrates, adisintegrant, a carbohydrate, and a coated carbohydrate. In someembodiments, an excipient system includes a mixture of at least threepolyols, such as mannitol, maltitol, and sorbitol, a disintegrant, apolyol, and a coated polyol.

In some embodiments, an excipient system includes a coated carbohydrateand a disintegrant. In some embodiments, an excipient system includes acoated polyol and a disintegrant. In some embodiments, an excipientsystem includes a coated carbohydrate, a carbohydrate, and adisintegrant. In some embodiments, an excipient system includes a coatedpolyol, a polyol, and a disintegrant. In some embodiments, an excipientsystem includes a carbohydrate and a disintegrant. In some embodiments,an excipient system includes a polyol and a disintegrant.

In some embodiments, an excipient system includes a glidant. Suitableglidants include but are not limited to silica gel, colloidal silica,fumed silica, precipitated silica, talc, and mixtures thereof. Theglidant component of the co-processed carbohydrate system preferably ispresent in a range of from about 0% to about 5% of the total weight ofthe system.

The silica gel acts to improve the flow properties of the compositionand minimize the amount of material that sticks to the punches and diesduring tableting. The colloidal silica acts to improve the flowproperties of the composition before it is tableted.

Formulation

In some embodiments, a pharmaceutical formulation includes an excipientsystem as described above. In some embodiments, a pharmaceuticalformulation includes a suitable amount of excipient system. In someembodiments, a pharmaceutical formulation includes about 20 wt % toabout 99 wt % excipient system. In some embodiments, a pharmaceuticalformulation includes about 20 wt % to about 95 wt % excipient system;about 25 wt % to about 90 wt % excipient system; about 25 wt % to about85 wt % excipient system; about 25 wt % to about 80 wt % excipientsystem; about 25 wt % to about 75 wt % excipient system; about 25 wt %to about 75 wt % excipient system; about 30 wt % to about 70 wt %excipient system; about 35 wt % to about 65 wt % excipient system; about40 wt % to about 60 wt % excipient system; about 45 wt % to about 55 wt% excipient system; or about 50 wt % excipient system.

In some embodiments, a pharmaceutical formulation includes an API.Suitable such APIs include but are not limited to those described in thePhysician's Desk Reference, 61st ed. Montvale, N.J.: Thomson PDR; 2007,which is incorporated by reference herein in its entirety. In someembodiments, a pharmaceutical formulation includes about 1 wt % to about75 wt % API; about 5 wt % to about 70 wt %; about 10 wt % to about 65 wt%; about 15 wt % to about 60 wt %; about 25 wt % to about 55 wt % API;about 30 wt % to about 50 wt % API; about 35 wt % to about 45 wt % API;about 37 wt % to about 43 wt % API; or about 40 wt % API.

In some embodiments, a pharmaceutical formulation includes suitablecomponents including but not limited to lubricants, flavors, sweeteners,and colors, in amounts appropriate to achieve the desired properties.

Solid Dosage Forms

In one embodiment of the present invention, the solid dispersionformulation is directly compressed into a solid dosage form (e.g., atablet) using a standard compression equipment (e.g., a tabletingpress). One embodiment of the directly compressed solid dosage form ofthe present invention dissolves or disintegrates within 10 minutes,preferably within less than 6 minutes. One embodiment of the directlycompressed solid dosage form of the present invention disintegrateswithin the stomach or intestine within 10 minutes, preferably withinless than 6 minutes.

In one embodiment of the present invention, the solid dispersionformulation is directly compressed into a swallow tablet or lozengeusing standard compression equipment (e.g., a tableting press). Oneembodiment of the swallow tablet or lozenge of the present inventiondissolves or disintegrates within 10 minutes, preferably within lessthan 6 minutes. One embodiment of the swallow tablet or lozenge of thepresent invention disintegrates within the stomach or intestine within10 minutes, preferably within less than 6 minutes.

In one embodiment of the present invention, the solid dispersionformulation is directly compressed into a solid dosage form (e.g., atablet) using a standard compression equipment (e.g., a tabletingpress). One embodiment of the directly compressed solid dosage form ofthe present invention interacts with saliva in the oral cavity of apatient and completely dissolves or disintegrates in the oral cavityinto an easily swallowable form within about 60 seconds.

In one embodiment of the present invention, the solid dispersionformulation is directly compressed into an orally dispersible tabletusing standard compression equipment (e.g., a tableting press). Oneembodiment of the orally dispersible tablet of the present inventioncompletely dissolves or disintegrates in the oral cavity within about 60seconds.

In one embodiment of the present invention, the solid dispersionformulation is directly compressed into a chewable tablet using standardcompression equipment (e.g., a tableting press). One embodiment of thechewable tablet of the present invention completely dissolves ordisintegrates in the oral cavity into within about 60 seconds.

In an embodiment of the invention, the solid dosage form completelydissolves or disintegrates within about 25 to 50 seconds after placingthe tablet in the oral cavity. In an embodiment of the invention, thesolid dosage form completely dissolves or disintegrates within about 5to 20 seconds after placing the tablet in the oral cavity. In oneembodiment of the present invention, the solid dosage form completelydissolves or disintegrates in the oral cavity in less than 60 seconds.In one embodiment of the present invention, the solid dosage formcompletely dissolves or disintegrates in the oral cavity in less than 50seconds. In one embodiment of the present invention, the solid dosageform completely dissolves or disintegrates in the oral cavity in lessthan 40 seconds. In one embodiment of the present invention, the soliddosage form completely dissolves or disintegrates in the oral cavity inless than 30 seconds. In one embodiment of the present invention, thesolid dosage form completely dissolves or disintegrates in the oralcavity in less than 20 seconds. In one embodiment of the presentinvention, the solid dosage form completely dissolves or disintegratesin the oral cavity in less than 10 seconds. In one embodiment of thepresent invention, the solid dosage form completely dissolves ordisintegrates in the oral cavity in less than 5 seconds.

In one embodiment, the solid dosage forms produced in the presentinvention preferably have a hardness (standard USP method) in the rangeof about 1 kP to about 50 kP and a friability (standard USP method) inthe range of about 0.01% to about 5%.

In one embodiment of the present invention, the solid dosage formsproduced have a hardness from about 7 to about 39.9 kP and a friabilityof less than about 0.5% and a disintegration of less than about 30seconds.

In one embodiment of the present invention, the solid dosage formsproduced have a hardness range of about 4.8 kP to about 34.1 kP and afriability of less than about 0.2% and a USP disintegration of less thanabout 60 seconds. In one embodiment of the present invention, the soliddosage forms produced have a hardness (standard USP method) in the rangeof about 3 kP to about 15 kP and a friability (standard USP method) inthe range of about 0.01% to about 2%, and would dissolve or disintegratein less than 60 seconds.

In some embodiments, a solid dosage form includes a solid dispersionwith a mixture of at least two carbohydrates. In some embodiments, asolid dosage form includes a solid dispersion with a mixture of at leasttwo polyols. In some embodiments, a solid dosage form includes a soliddispersion with a mixture of at least two sugars. In some embodiments, asolid dosage form includes a solid dispersion with a mixture of at leastthree carbohydrates. In some embodiments, a solid dosage form includes asolid dispersion with a mixture of at least three polyols. In someembodiments, a solid dosage form includes a solid dispersion with amixture of at least three sugars. Carbohydrates, including but notlimited to polyols and sugars, suitable for the solid dispersions of thepresent invention are described above. In some embodiments, a soliddosage form of the present invention includes a solid dispersionincluding mannitol and maltitol. In some embodiments, a solid dosageform of the present invention includes a solid dispersion includingmannitol and isomalt. In some embodiments, a solid dosage form of thepresent invention includes a solid dispersion including mannitol,maltitol, and sorbitol. In some embodiments, a solid dosage form of thepresent invention includes a solid dispersion including mannitol,isomalt, and sorbitol.

In some embodiments, a solid dosage form of the present inventionincludes a solid dispersion including mannitol, maltitol, and sorbitol.In some embodiments, a solid dosage form of the present inventionincludes a solid dispersion including mannitol, lactitol, and sorbitol.In some embodiments, a solid dosage form of the present invention doesnot include xylitol.

The highly compactable solid dispersions and excipient systems of thepresent invention may be used as a delivery platform for one or moreactive ingredients. One or more active ingredients may be mixed with thesolid dispersion and formed into a solid dosage form, such as a tablet.In another embodiment, additional ingredients such as a lubricant,flavor, color, or sweetening agent may also be added to the formulationand formed into a solid dosage form.

When the solid dosage form is placed in the oral cavity of a patient, itinteracts with saliva and rapidly dissolves or disperses in the oralcavity of the patient. As the solid dosage form dissolves in the oralcavity of the patient, it releases the one or more active ingredientscontained in the solid dosage form.

It will be apparent to one of skill in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of the present invention provided they comewithin the scope of the appended claims and their equivalents.

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all referenced publicly availabledocuments, including but not limited to a U.S. patent, are specificallyincorporated by reference.

EXAMPLES Example 1: Solid Dispersion of Three Co-Processed CarbohydratesWith Microcrystalline Plate Structure

Water is charged to an agitated jacketed mix tank, and the water heatedto 78-90° C. The following raw materials are added to the mix tank withagitation.

Material Amount in Kilos Percent of Saturation Mannitol 600 kilosMaltitol 10.6 Sorbitol 14.4 Purified Water 760 kilos Silicon dioxide Upto 1% as process aid

When the raw materials are in solution and at temperature, the solutionis spray dried by the following process.

A 7″ rotary atomizer is set-up with a feed pump and the ability torecycle smaller sized particles by fluid bed classification back to thespray drying chamber, as shown in FIG. 1 and described in Methods ofMaking-Co-Spray Dried section. The spray dryer parameters are asfollows: dryer inlet temperature 195-205° C.; fluid bed inlettemperature 74-122° C. (for monitoring purposes only); dryer outlettemperature 80-95° C. (target 89-92° C.); atomizer wheel speed11250-11600 rpm. The solution is sprayed into a drier outlet airtemperature of 85 to 90° C. The product Solid Dispersion A is collectedonce the system is stabilized and after approximately 25 kilos ofproduct is produced. The moisture content of the discharged productshould be less than 0.3%.

FIG. 2 is a SEM (magnification 2000×) of solid dispersion SolidDispersion A demonstrating the microcrystalline plate structure. FIG. 2clearly shows the plates in the microcrystalline plate structure. Inthis embodiment, the plates are less than 1 μm in thickness, as comparedto the 10 μm scale in FIG. 2 , and are arranged in layers. Each layercan be seen as a relatively continuous film. The layers are heldtogether by the attraction of surfaces that are comprised of a eutecticformed from the three polyols. It is believed that the microcrystallineplate structure is due to the difference in solubilities andconcentrations of the polyols.

Maltitol has the following chemical structure, with one glucose ring andone sorbitol moiety attached:

Notably, three of the five hydroxyls on attached sorbitol are facing upin the sorbitol structure giving the attached sorbitol a highly polararea facing up. Also based on the 1,4 linkage the sorbitol moiety isheld at an angle to the glucose ring.

At 80 C in solution Mannitol has a solubility of about 47.% in water,maltitol has a solubility of about 80% in water, and sorbitol has asolubility of about 92% in water In the drying process, based onsolubility and concentration used, mannitol will crystallize fromsolution first, and very early. The mannitol will form nuclei and alsogrow formed nuclei. Maltitol will begin to co-crystallize with mannitol,followed by the sorbitol component.

The center of the plates is composed of the high melting (thus high bondstrength) mannitol that crystallizes first and throughout the dryingprocess based on its close to saturation concentration in the solutionbeing dried. The entire particle by differential scanning calorimetry(DSC) is a single peak eutectic mixture with a crystalline core (vsthree peaks, one for each of the 3 polyols) called a fusion form as theheat of fusion of mannitol is slightly changed from an expected 293 J/gmto ˜280 J/gm but it's single melt point still is a characteristic betaor alpha mannitol melt point of ˜166 C. The formation forms aplasticized plate with an eutectic transition, which limits platethickness and also plate surface tackiness.

This eutectic surface generates a bond transition between layers that isweakly bounded, thus allowing low pressure fracturing. The thinness andplanar nature of the plates allow for fracture of crystal fragments inthe shape of splinters that can be seen in FIG. 3 . FIG. 3 is an SEM ofthe interior structure of a Solid Dispersion A tablet compressed at 20kN compression pressure broken in half. The width of the broken chips isless than a few microns in size and less than one micron in thickness.

To make the solid dosage form tablet in FIG. 3 , Solid Dispersion A wasblended in an 8 Quart Vee Mixer (Paterson-Kelley, East Strausburg, Pa.)with 1.5% magnesium stearate for 10 minutes. Tablets were made at aspeed of 26 RPM without use of pre-compression. A FFBE (flat-facedbeveled edge) 0.625 inch diameter tablet station was used on a MiniPress(Globe Pharma, New Brunswick, N.J.). The tablet weight was 1.0 gm.

The mannitol crystal ‘splinters” is a “moving unit” that is pushed intospaces that are still open in a tablet as pressure is applied. Theefficiency of moving to an area of lower pressure from an area of higherpressure gives the advantage of plastic deformation. These splintersmove to the tablet outer surface at low pressure and create a moredurable, lower friable surface.

As can be seen in FIGS. 4 and 5 , it was surprising that at 13 kNcompression force a hardness of 22 kP was found and a friability of lessthan 0.03%. What is even more surprising is the hardness increasedlinearly from 13 kN compression force applied to 33 kN compression forceand was at a maximum of 50 kP hardness at 33 kN compression pressurewith the friability remaining below 0.2%, even below 0.15% for theentire compression force range. The same process applied to othercompositions may result in lower hardness values. For example, in someembodiments, 97.7 wt % mannitol with 2.3% sorbitol exhibited a hardnessof 14 kP at 13 kN, and 90% mannitol with 10% sorbitol, co-spray dried,exhibited a hardness of 16 kP at 13 kN.

The increase in transition phase segmentation and surface orientation isevident in the almost 50 kP hardness generated for the Solid DispersionA at a pressure of 32 kN versus 32 kP for the 90% mannitol and 10%sorbitol spray dried product at 32 kN. The optimization of layering isseen also in the 6.04% maltitol/2.3% sorbitol product, which exhibited ahardness of 13 kP at a compression force of 13 kN and 44 kP at acompression force of 32 kN.

Table 3 below summarizes the physical characteristics of soliddispersion Solid Dispersion A.

TABLE 3 Characteristics of Tablets made from Solid Dispersion A TabletedSolid Dispersion A Radial USP Compression Mean STDEV Tensile Dis ForcePressure Hardness Hardness Thickness Strength Density Friability TimeNts KN Mpa kP N kP mm Sdev Mpa g/cm3 (%) (sec) 13161 13.16 67 21.8 213.30.472 4.516 0.0032 1.895 1.123 0.11 160 15032 15.03 76 25.5 250.0 0.5884.434 0.0074 2.262 1.142 0.14 180 18881 18.88 95 32.3 316.4 0.500 4.3030.0036 2.949 1.177 0.15 229 23135 23.14 117 37.9 371.1 0.670 4.1810.0069 3.561 1.209 0.13 396 27761 27.76 140 44.7 438.3 0.960 4.0990.0103 4.289 1.235 0.12 534 30718 30.72 155 48.5 475.6 1.023 4.0400.0057 4.721 1.250 0.13 529 33819 33.82 171 50.3 492.5 1.33 3.998 0.014.942 1.266 0.130 553

Example 2: Comparison of Solid Dispersion A With Microcrystalline PlateStructure With Other Excipients and Excipient Systems

Solid dispersion Solid Dispersion A, as described in Example 1, iscompared to the following excipient systems.

Product Components FIGS. 1) Mannogem ® EZ EP >98% mannitol and ~1% FIGS.grade (SPI Pharma) sorbitol 6A-6C 2) Mannogem ® EZ USP >96% mannitol and~2% FIGS. (SPI Pharma) sorbitol 6D-6F 3) Mannitol HS (SPI >86% Mannitoland ~12% FIGS. Pharma) sorbitol 6G-6I 4) Parteck ® M 200 EP >98%mannitol and <2% FIGS. grade (EM Merck, Germany) sorbitol 6J-6K

FIGS. 6A-6C show various magnifications of Mannogem® EZ-EP grade. FIGS.6D-6F show various magnifications of Mannogem EZ USP grade. FIGS. 6G-6Ishow various magnifications of Mannitol HS. FIGS. 6J-6K show variousmagnifications of Parteck® M200. FIGS. 7A-7C are SEMs of SolidDispersion A at various magnifications showing the microcrystallineplate structure.

The SEMs of the above spray-dried materials show crystalline structuresthat exhibit distinct differences based on the composition andconcentrations. The lower percentage of sorbitol (˜1%) in Mannogem EZ EPgrade results in a primary particle that is a segmented deposit ofcrystalline fragments. The droplets in the process of drying separatesinto narrow width crystalline surface fragments. The slightly higherlevel of sorbitol (˜2%) in Mannogem EZ USP grade results in a surface inwhich as the droplets dry they form a segmented deposit with morerounded edges. It is believed that the more rounded edges and thepuckered appearance of the deposit is due to the coalescence of mannitoland sorbitol at its edges. Mannitol HS, which has a much higher level ofsorbitol (˜12%), has a surface that is more continuous as evidenced byits smooth surface and rounded, merged edges. Droplets of Mannitol HSappear to be coalescing/merging to form a film deposit with the surfacesbelow with a tightened attachment. This film structure is furtherdemonstrated by the presence of 2 distinct peaks in a DSC scan.

The surface structure of Parteck® M200 (<2% sorbitol) appears to besimilar to Mannogem EZ EP grade with segmented deposits of crystallinefragments with some filamentous attachments.

In FIG. 8 , hardness is depicted as a function of compression force forcomparison of tableted Solid Dispersion A to Mannogem EZ and Parteck®M200. The filamentous structure of Parteck® M200 adds to itscompactability and its slope to be equivalent to Solid Dispersion A at˜1.3 kP/kN pressure. However in FIG. 9 , it is demonstrated thatParteck® M200 has a longer disintegration time than Solid Dispersion Aat lower pressure of force. It is thought that Solid Dispersion A ismoving at low pressure due to its microcrystalline plate structureversus Parteck® M200's structure that at similar low pressures isspreading the filamentous deposit into pores and filling them.

It is evident that the improvement gained via this invention is thedevelopment of a higher hardness with lower pressure without the loss ofdisintegration time. Another advantage of the present invention is theability to control the thickness of the microcrystalline platestructure. The earlier in the process the dispersed phase of the soliddispersion is co-crystallizing, the thinner the mannitol layer in themicrocrystalline plate structure. The later in the co-crystallizationprocess the thicker the mannitol layer. An additional advantage of thepresent invention is the low friability of the solid dosage forms. Thethinner the layer in the microcrystalline plate structure, the thinnerthe layer the smaller the pore the deforming plate can penetrate and themore rapidly will be the stress relief in the solid dosage form matrix.

The present invention also provides the advantage of controlling thetackiness of the surface composite. The dispersant component of thesolid dispersion can also be incorporated in a linear or non linearmatrix design. Non linear and angled is the 1,4 linked design oflactitol and maltitol and similar 1,4 linked polyols or disaccharides.

It is believed the glucose or galactose in the 1,4 linkage gets involvedin the growth of the mannitol matrix in the most rapidly growing Cdimension of the crystal pattern and segment, leaving the sorbitolportion of the disaccharide available in an angle plane to layer eithermannitol, sorbitol or a glucose or galactose portion of maltitol orlactitol in a crossed crystalline arrangement. Thus mannitol wants togrow in C direction and is blocked and starts to grow in the Adimension, its slowest growing crystal face. This leads to enough growthin A dimension to form a thick enough crystal plane in the C dimensionwhich is again blocked by attaching the glucose or galactose deposit.

A non linear model can be generated from the 1,6 linked format, which isthe less angular format. Monopolyols/saccharides and disaccharadies suchas 1,6 linked isomalt or similar 1,6 linked disaccharides can be used.

It is apparent the fragmented step arrangement of the non linear modelis not as likely. The structure of the composite will be stiffer withless in composite area of non-crystalline transition.

Without limiting the scope of the invention, FIG. 10 depicts a possiblestructural explanation for the functionality of performance of soliddispersion Solid Dispersion A. The structure of the microcrystallineplate structure consists of a core, a single or multiple steppedtransition layer and a surface layer. The core is a mannitol crystalwhich is a naturally thin crystal structure of the Alpha and Betacrystal form. Mannitol in either Alpha or Beta form is shaped like afeather, long in the C direction, not very wide in the B direction andthin in the A direction. The transition layer above the mannitol core issegmented. The segments are in the stepped configuration are due to theglucose ring of in this example maltitol which incorporated into thefastest growing C direction plate. Angled off this glucose portioninclusion and oriented in the A growth surface is the sorbitol portionof the maltitol. The sorbitol portion of maltitol insertion in the Adirection attracts mannitol to it in the transition layer. As sorbitolin maltitol is linked in the sorbitol 4 position the sorbitol attractionis maximized to take advantage of sorbitol high dielectric constant of35.5 (Handbook of Chemistry and Physics, 84^(th), D. Lide CRC press).The draw of mannitol firms up the film in the C direction plasticize itand yet allows the glucose portion to segment the transition layer fortablet pressure deformation. In the surface layer sorbitol is now alsoco-crystallizing with the maltitol and mannitol. The sorbitol adds inwith its higher polar side down on the maltitol sorbitol inclusion inthe A surface direction. This given a lower surface polar bond tackingenergy from the weaker polar side now up to the A surface allowing lowerpressure dissociation of the microplate during tableting.

Example 3: Microcrystalline Plate Structure Bond Strength

In one embodiment, a particle of the solid dispersion consists ofmicrocrystalline plates. The microcrystalline plates have three distinctzones, the core, a transition zone and a surface zone. To make aparticle these micorplates are stacked in layers one on another like a“onion”. The particles in some embodiments are hollow. Thus the “onion”layer of microplates is on the exterior surface like on a bubble, withthe “onion” layered microplates being the layers in the skin.

Two factors in tabletting are used to form bonds and make a tabletharder as a greater compression force is applied. One factor is moresurface coming in close contact (loss in porosity) and bonding and thesecond is the bond strength per unit surface of the formulation. Twospecial conditions are needed for hardness of tablets. The bond strengthper surface area needs to be high, and the area of contact per totalsurface area present in material should be high.

The bond strength between the microplates is controlled by the surfacecomposition of the microplate. At low pressure the interphase betweenmicroplate surfaces becomes a fracture line generating microplatesplinters as can be seen in the FIG. 3 of Solid Dispersion A tabletcross section SEM. The reason for the splintering is the weakenedmicroplate interphase bond, the microplate thinness and the continuous,yet fragmented structural nature of the microplate.

From a functional view the lack of change in friability and thedurability of the tablet surface or skin are also evidence of thebonding weakness of the microplate. As the porosity of the tablet isclosing from 13 kN force applied to 33 kN force the low friability andhigh durability of the tablet surface is developed and remains unchangedeven at the higher forces applied.

To calculate porosity in the tablet, the density of the tablet iscompared in a ratio of the true density of the tableting materials.Solid Dispersion A true density was measure using a Quantachrome (PalmBeach, Fla.) helium pycnometry at 1.435 gm/ml. Tablet density is foundby using tablet weight and dividing by tablet volume. Tablet volume istablet thickness and the tablet diameter 15.87 mm (0.625 inches) tocalculate the volume of a cylinder. % Porosity is the 1−(tabletdensity)/(1.435 gm/ml)*100.

An estimate of bonding strength per unit area can be obtained bycalculating the radial tensile strength at zero porosity, a point whereall surfaces are theoretically touching.

Radial tensile strength (RTS) was calculated for the tablet (see USP 32,Chapter 1217 for test and calculation method). FIG. 11 depicts the RTSas a function of porosity. The RTS strength at zero porosity of 8.6 Mpaas seen in FIG. 11 is substantial, producing a tablet with a breakingforce of 85 kP. See FIG. 12 for plot of % porosity versus breakingforce. Most one gram tablets as chewable as 0.625 inch diameter FFBEwould be considered too hard at 20 kP breaking force.

In FIG. 13 for the same tablet run featuring % porosity versus very highhardness from 13 kN to 35 kN compression force it is very obvious that avery low friability of <0.16% is achieved at 13 kN force and ismaintained at pressure up to 33 kN force range (R²=0.0014). To achievesuch low friability at such a low pressure the bond strength betweenplates in the surface zone of the microplate must be low to allowfracture, yet to achieve such a high bond per unit area of 85 kp thebond formation in the transition zone deformation must be high. Webelieve this is accomplished in four ways. 1) Microplates surface zonehas low bond energy allowing the plates to fracture at low pressure(FIG. 3 of Solid Dispersion A tablet cross section shows fracturedplates). 2) The plates are very thin and thus can move into small spacesin tablet that are open. 3) The transition zone is deformable underpressure to give a high bond per unit area. 4) The core of themicrocrystal is a very durable crystal that forms the hardness of thetablet in combination to 3 developing the deformation and total surfaceto surface bond at 85 kP.

In this embodiment of the present invention the breaking force is 85 KP,which is an exceptionally hardened tablet at zero porosity. Most amazingis the linear response to strength increase with force applied, whichgenerally, means the only factor changing is the increase in tabletstrength through bond formation. With bond strength per surface areafixed at 8.6 Mpas, the factor changing in a linear fashion is the lossin porosity and a greater amount of surface coming in close contact andbonding. This very high bonding energy per unit surface allows highertablet strength with less surface contact area. Thus dilutability byadding actives and other needed ingredients still allows for productionof acceptable tablets both in durability and hardness.

Example 4: Uniformity of Densification

Solid Dispersion A, as described in Example 1, is formulated andcompared with Fast Flo® Lactose (Wisconsin Dairies, Appleton, Wis.) in a500 mg acetaminophen tablet formulation in an 850 mg tablet. Theformulations have Compap L a direct compression grade of acetaminophenby Covidien (St. Louis, Mo.) at 65.65%, Copovidone S-630 (ISP, Wayne,N.J.) at 3%, Crosspovidone XL-100 (ISP, Wayne, N.J.) at 2% and MagnesiumStearate of Covidien (St. Louis, Mo.) at 1.5%. Tablets were made on aMinipress II made by Globe Pharma (New Brunswick, N.J.) using0.3125×0.72 caplet shaped tooling at 21 RPM.

In FIG. 14 , the 27.85% of Solid Dispersion A added to the mixture showsa linear rise in hardness of tablet with increasing compression force.Note at the same level, 27.85% of Fast Flo® lactose the hardness of thetablets is linear only up to 10 kN of force. Above 10 kN of force thelinearity is lost and hardness does not increase.

In FIG. 15 , the friability of the Solid Dispersion A formulation iscompared with FastFlo® lactose formulation. The friability of SolidDispersion A is well below 1% in the formulation and stays below 1% forthe entire compression force profile for Solid Dispersion A. This is notthe case for Fast Flo® lactose which at 12 kN the friability of thetablet is increasing, giving evidence to the failing durability of thetablet structure. This durability failure results from a build up ofinternal stress with the higher compaction pressures and the resultantelastic recovery of the structure. Solid Dispersion A under pressure isflowing into unoccupied spaces in the tablet matrix relieving thepressure build up. Solid Dispersion A based upon the linearity ofhardness with pressure and maintenance of durability in the friabilitytest with pressure build up demonstrates the ability of Solid DispersionA to flow from areas of higher pressure to areas of lower pressure in alinear manner.

Note the flat line for friability does not increase with compressionforce. Lactose shows low friability at lower pressure, but due topressure build up in the structure the tablet ruptures at higherpressure. Additionally, the hardness of Solid Dispersion A climbslinearly with compression force. The Fast Flo® lactose does not climb inhardness after an increase in pressure due to the build up ofdensity/pressure centers without forming more bond strength. The SolidDispersion A plates are still moving into open smaller spaces at higherpressure and creating bonding surfaces where pores were oncepresent/open.

Example 5: Fast Disintegrating Excipient System and PharmaceuticalFormulation

Excipient System A Ingredient # Ingredient Name Wt % 1 Solid DispersionA 49 2 Mannogem EZ 15 3 Silicon Dioxide 1 4 Mannogem EZ (about 99 wt %)coated with 20 soluble polymer material (about 1 wt %) 5 Crospovidone XL15 Formulation A Ingredient # Ingredient Wt % 1 Taste-maskedacetaminophen (93%) 38.4 2 Excipient System A (as described above) 45.93 Natural peppermint flavor 2 4 Sucralose 1.25 5 Silicon dioxide 1 6Plasdone ® S-630, copovidone 3 7 Plasdone ® XL, crospovidone 5.9 8 Bluelake 5516 0.05 9 Sodium stearyl fumarate 2.5

In order to make a 60 kg batch of Excipient System A, 29.4 kg ofpreviously co-processed mannitol (about 96%), maltitol (about 1.7%), andsorbitol (about 2.3%) (SPI Pharma; Wilmington, Del.), 2.) 9.0 kg ofMannogem EZ (SPI Pharma; Wilmington, Del.), 3.) 0.6 kg of Syloid 244FPEU (Grace Davison; Colombia, Md.), 4.) 12.0 kg of EZS1 (SPI Pharma;Wilmington, Del.), 5.) 9.0 kg of crospovidone XL (Nanhang; Hangzhou,China) were weighed out using an electronic scale. The mannitol,maltitol, sorbitol, Mannogem EZ, EZS1 and crospovidone XL were screenedthrough a 48″ or 60″ Sweco screening apparatus (Sweco; Florence, Ky.)assembled with a #30 stainless steel square hole mesh (Sweco; Florence,Ky.). Syloid 244FP EU was passed through a #20 stainless steel handscreen with square hole mesh (Custom Advanced; Webster, Tex.). Afterscreening, all components were collected. The screened materials werecharged by hand into a 10 cubic foot V-blender (Patterson-Kelly; EastStroudsburg, Pa.) in the following order: 15.0 kg of co-processedmannitol, maltitol and sorbitol, 0.6 kg of Syloid 244FP EU, 14.4 kg ofco-processed mannitol, maltitol, sorbitol, 9.0 kg of Mannogem EZ, 9.0 kgcrospovidone XL, and 12.0 kg of EZS1. The materials were blended inV-blender set at 25 rpm for a total of 15 minutes. The blend wasdischarged from the bottom port of V-blender into a double polylineddrum. 2.5% of sodium stearyl fumarate was blended in prior to tableting.

In order to make 1 kg of Formulation A which is subsequently compressedinto a 500 mg APAP orally disintegrating tablet (ODT) with a totalweight of 1400 mg, 384 g of taste-masked Acetaminophen (Eurand; Yardley,Pa.), 2.) 459 g of Excipient A (SPI Pharma; Wilmington, Del.), 3.) 20 gof Natural Peppermint flavor (Givaudan; Cincinnati, Ohio), 4.) 12.5 g ofSucralose (Tate & Lyle; London, England), 5.) 10 g of silicon dioxide(Grace Davison; Colombia, Md.), 6.) 30 g Plasdone S-630 (ISP; Wayne,N.J.), 7.) 59 g of Crospovidone XL (Nanhang; Hangzhou, China), 8.) 0.5 gBlue lake 5516 (Colorcon; Harleysville, Pa.), 9.) and 25 g sodiumstearyl fumarate (SPI Pharma; Wilmington, Del.) were weighed out usingan electronic scale. Subsequent to weighing, ingredients 1, 2, 3, 4, 5,6, and 7 were screened through a #20 stainless steel screen withsquare-hole mesh (Custom Advanced; Webster, Tex.). Ingredients 8 and 9were co-screened through a #20 stainless steel screen with square-holemesh (Custom Advanced; Webster, Tex.). After screening, all ingredients,except ingredients 8 and 9 (already co-screened) by hand, were placedinto an 8-quart V-blender (Patterson-Kelley; East Stroudsburg, Pa.), inthe following order: total of 1, total of 2, total of 3, total of 4,total of 5, total of 6 and total of 7. Materials were blended inV-blender set at 25 rpm for a total of 15 minutes. To the resultantblend, the co-screen of ingredients 8 and 9 were added and blended foran additional 5 minutes in the 8-quart V-blender at 25 rpm. The blendwas discharged from the bottom port of the V-mixer into a polyline bag.The collected blend was placed into the hopper of a GP-8 rotary tabletpress (Globe Pharma; New Brunswick, N.J.) outfitted with one station of0.625″ FFBE “D” tool upper punch, lower punch, and die (NatoliEngineering; St. Charles, Mo.). The blend was tableted into 1400 mgweight tablets at 25 rpm with 2 kN of pre-compression, adjusting themain compression to obtain a tablet hardness of 6 to 7 kP.

A relationship between disintegration and friability as a function ofhardness for tabletted Excipient System A is shown in FIG. 16 .

As illustrated in FIG. 16 , an excipient system of some embodiments ofthe present invention exhibits a lower dependence of disintegration timeand friability on hardness. In some embodiments, an excipient system ofthe present invention may disintegrate rapidly at high hardness values.In some embodiments, an excipient system of the present inventionrapidly develops a creamy mouth feel upon disintegration. As illustratedin FIG. 16 , an excipient system of the present invention mayunexpectedly disintegrate in less than about 30 seconds at a hardnessvalue of about 39.9 kP, and in some embodiments can rapidly develop acreamy mouth feel upon disintegration. In some embodiments, an excipientsystem exhibits desirable disintegration times and friability values ata wide range of hardness values. In some embodiments, an excipientsystem exhibits a low increase in disintegration time per increase inhardness values.

Example 6: Fast Disintegrating Excipient System B and PharmaceuticalFormulations

Coating Solution B QTY Ing. # ITEM (MFG, Location) Percent (Kg) 1Plasdone S-630 (ISP, Colombia, MD) 11.98 9.2 2 Purified Water N/A 88.0267.6 Total Wt. (Dry Basis) 11.98% 9.2

67.6 kg of purified water was charged into a solution tank, outfittedwith an agitator. While agitating the purified water, Plasdone S-630 wasslowly added to the tank. Agitation was continued until a uniformdispersion of the Plasdone S-630 in purified water was achieved. CoatingSolution B was used within 12 hours of obtaining the uniform dispersion.The solution was kept under continuous agitation during subsequentprocessing steps.

Coated Solid Dispersion A QTY Ing. # ITEM (MFG, Location) Percent (Kg) 1Solid Dispersion A (SPI, Wilmington, DE) 92.29 400 2 Coating Solution B(SPI, Wilmington, DE) 7.71 33.4 Total Wt. (Dry 93.22% (Dry 404 Basis)weight of 404 kg/ 433.4 kg)

400 kg of Solid Dispersion A was weighed out and screened using a 48 or60″ Sweco equipped with a #16 stainless steel screen with square holes.The screened Solid Dispersion A was charged into the fluid air bowl of aFluid Air 1000. Spray nozzles were 0.066″-0.068″ bore set at extendedfrom the cap. The liquid nozzle manifold was set up with the standardextension (10.5″). The Fluid Air 1000 was operated in the followingmanner: airflow of 1500-3000 SCFM (target of 2000 SCFM), inlettemperature of 75° C.-100° C. (target 90° C.), solution spray rate of0.5-2.0 kg/min (target 1.1 kg/min), atomization air pressure at 50 PSIG,approximate spraying time was 17-66 minutes. The product temperature wasallowed to reach at least 30° C. prior to spraying solution. 33.4 kg ofsolution was sprayed on in approximately 17-66 minutes (target 30minutes at 1.1 kg/min). The filters were manually purged for at least 5minutes, if necessary, to maintain the minimum air flow. The granulationwas dried to a product temperature of 35° C.-50° C. (target of 45° C.).When the product temperature reached approximately 45 ° C., a sample(2.0g-3.0 g) was tested for moisture content. Park was pressed on thefluid bed and the filters manually purged while testing the moisture.Continued to dry and sample at approximately 10 minute intervals untiltarget moisture (target of <1.0%) was reached. When the moisture was<1.0%, the fluid bed was shutdown and the product cooled to 35° C. Thefilters were manually purged for at least 5 minutes. The resultingproduct, Solid Dispersion B, was sifted through a 48″ or 60″ Swecoequipped with a #16 stainless steel screen with square holes. Theproduct was packaged in double poly-lined drums.

Excipient System B QTY Ing. # ITEM (MFG, Location) Percent (Kg) 1 SolidDispersion A (SPI Pharma, 64.54 68.4 kg Wilmington, DE) 2 CrospovidoneXL (Nanhang Ind. 15.13 16.0 kg Co., Hangzhou, China) 3 Coated SolidDispersion A (SPI Pharma, 20.17 21.4 kg Wilmington, DE) 4 Syloid 244 FPEU (Grace Davison, 0.16  0.2 kg Columbia, MD) Total Wt. (Dry Basis) 100 106 kg

The above listed ingredients were weighed in the amounts indicated on anelectronic balance. Subsequent to weighing, ingredients 1, 2, and 3 werescreened through a previously assembled 48″ or 60″ Sweco screeningapparatus (Sweco; Florence, Ky.) assembled with a #20 stainless steel(Sweco; Florence, Ky.) square-hole mesh. Subsequent to weighing,ingredient 4 was passed through a #20 stainless steel hand screen withsquare-hole mesh (Custom Advanced; Webster, Tex.). After screening, allcomponents were collected in separate, labeled 37×80×0.0035 NaturalCo-ex polyethylene bags. The weighed and screened ingredients werecharged by hand into a 10 cubic foot V-blender (Patterson-Kelly; EastStroudsburg, Pa.) in the following order: 1) 34.2 kg of Solid DispersionA, 2) 0.16 kg of Syloid 244 FP EU, 3) 20.17 kg of Solid Dispersion B, 4)15.13 kg of Crospovidone XL, and 5) 34.2 kg of Solid Dispersion A.Materials were blended in V-blender set at 25 rpm for a total of 15minutes. Blend was discharged from bottom port of V-blender into adouble polylined drum.

160 mg Acetaminophen (APAP) Orally Disintegrating Tablet Taste-masked28.55% Acetaminophen (93.4% APAP) Excipient System B 66.20% Sucralose1.25% Bubblegum Flavor 2.00% Sodium stearyl fumarate 2.00%

For a batch size of 1000 g, the above ingredients were weighed andseparately screened through a #20 stainless steel square hole mesh. Eachingredient, except the sodium stearyl fumarate, was placed in an 8-quartV-blender and mixed for 15 minutes at a speed of 25 rpm. After 15minutes, the sodium stearyl fumarate was added to the blend and mixedfor 5 additional minutes at a speed of 25 rpm. The resultant blend wasemptied from the bottom discharge port of the blender into anappropriate plastic bag. The blend was placed in the hopper of a GP-8instrumented tablet press outfitted with 0.5″×0.5″ arc square punch “D”tool set (upper punch, lower punch, and die) with a cup depth of 0.0730″(Hob#104152, Natoli Engineering, St. Charles, Mo.) and compressed into600 mg tablets at a rotary speed of 36.7 rpm with a pre-compressionforce of 1 kN and to a tablet hardness of 5-7 kP as determined by aModel 6D Dr. Schleuniger tablet hardness tester.

500 mg Acetaminophen (APAP) Orally Disintegrating Tablet Taste-masked38.40% Acetaminophen (93.4% APAP) Excipient System B 44.40% PeppermintFlavor 2.00% Sucralose 1.50% Sodium stearyl fumarate 2.50% CrospovidoneXL 4.20% Microcrystalline Cellulose-101 7.00%

For a batch size of 500 g, the above ingredients were weighed andseparately screened through a #20 stainless steel square hole mesh. Eachingredient was placed in an 8-quart V-blender and mix for 15 minutes ata speed of 25 rpm, except for the sodium stearyl fumarate. After 15minutes, the sodium stearyl fumarate was added to the blend, and blendmixed for 5 additional minutes at a speed of 25 rpm. The resultant blendwas emptied from the bottom discharge port of the blender into anappropriate plastic bag. The blend was placed in the hopper of a GP-8instrumented tablet press outfitted with a 0.66″×0.66″ Arc Square “D”tool set (upper punch, lower punch, and die) with a cup depth of 0.0320″(Hob#105192, Natoli Engineering, St. Charles, Mo.) and compressed into1400 mg tablets at a rotary speed of 25 rpm with a pre-compression forceof 2 kN and to a tablet hardness of 5-7 kP as determined by a Model 6DDr. Schleuniger tablet hardness tester.

10 mg Loratidine Orally Disintegrating Tablet Loratidine 10.00%Excipient System B 84.50% Bubblegum flavor 2.00% Sucralose 1.00% SodiumStearly Fumarate 2.50%

For a batch size of 500 g, the above ingredients were weighed, andseparately screened through a #20 stainless steel square hole mesh. Eachingredient, except the sodium stearyl fumarate, was placed in an 8-quartV-blender and mixed for 15 minutes at a speed of 25 rpm. After 15minutes, the sodium stearyl fumarate was added to the blend, and mixedfor 5 additional minutes at a speed of 25 rpm. The resultant blend wasemptied from the bottom discharge port of the blender into anappropriate plastic bag. The blend was placed in the hopper of a GP-8instrumented tablet press outfitted with a 0.25″ FFBE set (upper punch,lower punch, and die) and compressed into 100 mg tablets at a rotaryspeed of 25 rpm and to a tablet hardness of 1-3 kP as determined by aModel 6D Dr. Schleuniger tablet hardness tester.

Example 7: Manufacturing of 500 mg Acetaminophen Caplet-Shaped SwallowTablets With Solid Dispersion A

For a 2.0 kg batch of a 500 mg acetaminophen tablet with SolidDispersion A, the following ingredients were weighed out: 1) 557 g ofSolid Dispersion A (SPI Pharma; Wilmington, Del.), 2) 1313 g of Compap L(Covidien, St. Louis Mo.), 3) 60 g of Plasdone S-630 (ISP Corp, Wayne,N.J.), 4) 40 g of Crospovidone XL-100 (Nanhang, Hangzhou, China) and 5)30 g of Magnesium Stearate (Covidient St. Louis, Mo.). Subsequent toweighing, the ingredients were screened through US #20 stainless steel(Sweco; Florence, Ky.) square hole mesh. The weighed and screenedingredients were charged into a 8 quart V-blender (Patterson-Kelly; EastStroudsburg, Pa.) in the following order: one half of 1, total of 2,second half of 1, total of 3, and total of 4. The material was blendedin V-blender set at 25 rpm for a total of 15 minutes. Ingredient 5 wasadded and blended an additional 3 minutes. The blend was discharged fromthe bottom port of V-blender into a double polylined drum.

The 500 mg acetaminophen caplet tablets with a total weight of 850 mgwere compressed as follows. The blend was placed into the hopper of aGP-8 rotary tablet minipress (Globe Pharma; New Brunswick, N.J.)outfitted with at least one station of 0.3125″ by 0.720″ keyed D toolsupper punch, lower punch, and die (Natoli Engineering; St. Charles,Mo.). The blend was tableted into 850 mg weight tablets at 25 rpm withup to 2 kN of pre-compression, adjusting the main compression to obtaina tablet hardness of 6 to 28 kP as desired. Above 7.5 kN compressionpressure, the friability is less than 0.5% and at maximum pressure of 22kN the hardness is 28 kP and friability is <0.4%.

Example 8: 1000 mcg B12 Lozenge Formulation With Solid Dispersion A

Ing. # Component % g/blend 1 Vitamin B12 (1% in mannitol) 21.51 107.53 2Solid Dispersion A 54.59 272.97 3 Sorbitab SD 250 20.00 100.00 4Sucralose 0.40 2.00 5 Lubripharm 3.00 15.00 6 Grape Flavor 0.10 0.50 7Purple Lake 0.40 2.00 Total 100 500

In order to manufacture Vitamin B12 lozenges containing 1000 mcg ofVitamin B12 in a 465 mg lozenge, the ingredients were first weighed onan electronic balance according to the table. All ingredients werepassed through a #20 stainless steel mesh with square holes. Allingredients, except for ingredient #5, were blended in an 8-quartV-blender at 25 rpm for 15 minutes. Subsequent to blending, ingredient#5 was added to blend 1, and mixed for 5 minutes in the 8-quart blenderat 25 rpm for 5 minutes. The resultant blend was removed through theinferior discharge port of the blender into an appropriate plastic bag.The blend was introduced into the hopper of a GP-8 instrumented tabletpress outfitted with an 11.1-mm FFBE “D” tool punch set (upper, lower,and die). The blend was compressed into 465 mg weight lozenges at arotary speed of 25 rpm and to a tablet hardness of 14-18 kP.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention shown inthe specific embodiments without departing form the spirit and scope ofthe invention as broadly described. Thus, it is intended that thepresent invention cover the modifications and variations of the presentinvention provided they come within the scope of the appended claims andtheir equivalents.

What is claimed is:
 1. A solid dispersion comprising a combination of atleast three co-processed carbohydrates with different solubilitiesand/or concentrations, wherein the solid dispersion has amicrocrystalline plate structure.
 2. The solid dispersion of claim 1,wherein the microcrystalline plate structure has a thickness of about0.1 microns to about 5 microns.
 3. The solid dispersion of claim 1,wherein the at least three co-processed carbohydrates are polyols. 4.The solid dispersion of claim 3, wherein the polyols are selected fromthe group consisting of mannitol, sorbitol, maltitol, lactitol, xylitol,erythritol, isomalt, and mixtures thereof.
 5. The solid dispersion ofclaim 3, wherein the polyols comprise a first polyol present in anamount of about 70 wt % to about 99.5 wt %, a second polyol present inan amount of about 0.5 wt % to about 30 wt %, and a third polyol presentin an amount of about 0.5 wt % to about 30 wt %.
 6. The solid dispersionof claim 5, wherein the first polyol is mannitol, the second polyol ismaltitol and the third polyol is sorbitol.
 7. The solid dispersion ofclaim 5, wherein the first polyol is mannitol, the second polyol islactitol and the third polyol is sorbitol.
 8. The solid dispersion ofclaim 1, wherein the solid dispersion is coated.
 9. The solid dispersionof claim 1, wherein the at least three co-processed carbohydrates arecoated.
 10. The solid dispersion of claim 1, wherein the at least threeco-processed carbohydrates are co-spray dried.
 11. The solid dispersionof claim 1, further comprising a glidant.
 12. The solid dispersion ofclaim 11, wherein the glidant is selected from the group consisting oftalc, colloidal silica, silica gel, fumed silica, precipitated silica,and combinations thereof.
 13. The solid dispersion of claim 1, wherein amelting point of the solid dispersion is not lowered by more than 5° C.than melting point of carbohydrate with the highest concentration. 14.The solid dispersion of claim 1, wherein a heat of fusion of the soliddispersion is not reduced by more than 40 J/gm than heat of fusion ofcarbohydrate with the highest concentration.
 15. A solid dosage formcomprising a solid dispersion which comprises a combination of at leastthree co-processed carbohydrates with different solubilities and/orconcentrations, wherein the solid dispersion has a microcrystallineplate structure.
 16. The solid dosage form of claim 15, furthercomprising an active ingredient.
 17. The solid dosage form of claim 16,wherein the active ingredient is coated.
 18. The solid dosage form ofclaim 16, wherein the active ingredient is uncoated.
 19. The soliddosage form of claim 16, wherein the solid dosage form further comprisesa lubricant, optionally a disintegrant, optionally a glidant, optionallya sweetner, optionally a flavor, optionally a color, and optionallyother excipients.
 20. The solid dosage form of claim 19, wherein thedisintegrant is selected from the group consisting of crospovidone,alginic acid, croscarmellose sodium, guar gum, microcrystallinecellulose, polacrilin potassium, powdered cellulose, sodium alginate,and sodium starch glycolate, and combinations thereof.
 21. The soliddosage form of claim 15, wherein the solid dosage form has acompactability as defined by a hardness from about 22 kP to about 50 kPwhen about 13 kN to about 35 kN of compression force is applied.
 22. Thesolid dosage form of claim 15, wherein the solid dosage form has adurability as defined by a friability of about 0.5% or less when about13 kN to about 35 kN of compression force is applied.
 23. The soliddosage form of claim 15, wherein the at least three co-processedcarbohydrates are polyols.
 24. The solid dosage form of claim 15,wherein the at least three co-processed carbohydrates are coated. 25.The solid dosage form of claim 15, wherein the solid dispersion iscoated.
 26. The solid dosage form of claim 15, wherein themicrocrystalline plate structure has a thickness of about 0.5 microns toabout 5 microns.
 27. The solid dosage form of claim 15, wherein the atleast three co-processed carbohydrates are co-spray dried.
 28. The soliddosage form of claim 15, further comprising a glidant.
 29. The soliddosage form of claim 28, wherein the glidant is selected from the groupconsisting of colloidal silica, silica gel, precipitated silica, fumedsilica, talc and combinations thereof.
 30. The solid dosage form ofclaim 23, wherein the polyols are selected from the group consisting ofmannitol, sorbitol, maltitol, lactitol, xylitol, erythritol, isomalt,and mixtures thereof.
 31. The solid dosage form of claim 16, wherein thesolid dosage form has a hardness of about 1 kP to about 50 kP.
 32. Thesolid dosage form of claim 16, wherein the solid dosage form has afriability of about 0.01% to about 5%.
 33. The solid dosage form ofclaim 19, wherein the solid dosage form is a fast disintegrating tabletor a chewable.
 34. The solid dosage form of claim 33, wherein the soliddosage form disintegrates in oral cavity in less than about 60 seconds.35. The solid dosage form of claim 16, wherein the solid dosage form isa swallow tablet or a lozenge.
 36. The solid dosage form of claim 35,wherein the solid dosage form disintegrates in less than 10 minutes. 37.The solid dosage form of claim 23, wherein the polyols comprise a firstpolyol present in an amount of about 70 wt % to about 99.5 wt %, asecond polyol present in an amount of about 0.5 wt % to about 30 wt %,and a third polyol present an amount of about 0.5 wt % to about 30 wt %.38. The solid dosage form of claim 37, wherein the first polyol ismannitol, the second polyol is maltitol and the third polyol issorbitol.
 39. The solid dosage form of claim 37, wherein the firstpolyol is mannitol, the second polyol is lactitol and the third polyolis sorbitol.